Absorbent ingestible agents and associated methods of manufacture and use

ABSTRACT

Appetite suppression and weight management achieved through pre-meal ingestion of temporary gastric bulking agents in the form of superabsorbent polymer hydrogels (SAPHs) selected from among a group consisting of crosslinked polycarboxylic acid moieties is described. The preferred compositions and manufacturing methods of ultrapure preparations of ingestible forms; as well as the preferred methods of use, dosage and administration; distribution and delivery of SAPH materials are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

Under 35 U.S.C. § 119(e) this application claims the benefit of U.S.Provisional Application Ser. No. 61/026,183 filed Feb. 5, 2008;entitled: Polymeric Agents and Associated Methods of Use for AppetiteSuppression and Weight Management; and U.S. Provisional PatentApplication Ser. No. 61/059,420 filed Jun. 6, 2008; entitled: IngestibleSAPH Mixtures with Improved Water-Swelling Characteristics; thedisclosures of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates to compositions and methods of administeringingestible forms of absorbent polycarboxylic acid polymers capable ofabsorbing large amounts of water in the gastric environment and whichare well suited for use as temporary pre-meal gastric bulking agentsdesigned to maximally suppress appetite thus assisting in bothshort-term weight loss as well as long-term weight management.

BACKGROUND

Widespread obesity and excessive weight gain have become widelyrecognized as an emerging global pandemic. Data recently published bythe World Health Organization estimates that in 2007, 1.6 billion people(one in four) were overweight or obese. Four hundred million of thesewere children. Modern societies are being crippled with the associatedcosts of overburdened healthcare systems that are crumbling beneath theweight of out-of-control medical costs associated with managing thenumerous life-threatening and often fatal diseases associated withexcessive weight. Type 2 diabetes, certain cancers, stroke,hypertension, age-related eye diseases, along with heart, liver andkidney disease are significantly prevalent co-morbid conditions thatplague this population.

Weight management was once considered only an issue of vanity. Now ithas escalated into a health crisis of unprecedented proportion.Currently, thousands of products and technologies have beencommercialized to assist overweight and obese people in their goal tolose and manage their weight. However, the issue of residualpost-prandial hunger remains an unsolved and fundamental issue for mostcalorie-restricted diets and weight loss plans. Despite the best ofintentions, the “battle of the bulge” is rarely won. The seeds of defeatlay in the fact that weight control is regulated by numerous redundanthormonal systems that are dedicated to preserving weight. In addition,calorie restriction in human physiology causes the generation of“hunger” pains, headaches, nausea and other deprivation sensations whichare often so severe that it becomes nearly impossible for most dietingpersons to control their urge to eat through the sheer exercise of theirwillpower alone.

Although numerous attempts have been made to promote a feeling of“fullness” or satiety, when the stomach is not in fact filled with food,each proposed means has encountered difficulties in achieving a desiredlevel of practical success. High fiber diets require the consumption ofsubstantial volumes of material leading to large increases inflatulence, abdominal discomfort and increased elimination volumes.Central nervous system stimulants have severe and occasionally fatalside effects. Thickening agents and rheological modifiers have minimalefficacy. Surgical procedures, while often effective, are risky and veryexpensive.

Therefore, there exists in the art an ongoing need for safe andeffective compositions and methods that allow individuals to reducecaloric intake to lose weight while also minimizing the residual hungerwhich leads to a relapse of overeating. The present invention seeks toaddress one or more of these needs in the art.

SUMMARY

This invention relates to the field of hunger management, particularlyto ingestible compositions and methods for weight-loss and weightmanagement. In certain aspects the invention encompasses ultrapurebio-inert super-absorbent polymer hydrogel (SAPH) or gastric bulkingagent compositions that once ingested, aid in temporarily suppressingappetite and/or promoting a feeling of early satiety by mechanicallyoccupying gastric volume and or modifying the hormonal milieu thatcontrols satiety in persons seeking to reduce their caloric intake bydownsizing their meal portion sizes with a reduced or absent feeling ofresidual hunger.

In another aspect, the invention encompasses methods for controllingappetite comprising administering to an individual or consuming aneffective amount of an ingestible super-absorbent polycarboxylic acidpolymer, wherein the polymer absorbs water in the gastric environment.In certain aspects the methods include administering a SAPH or bulkingcomposition of the invention as a temporary pre-meal gastric bulkingagent to suppress appetite, and therefore, assist in weight managementand/or promote a feeling of early satiety in an individual. In stillother aspects the invention relates to methods for reducing caloricintake in an individual comprising administering to an individual orconsuming an effective amount of the polycarboxylate composition of theinvention.

In any of the aspects or embodiments described herein, an effectiveamount of the SAPH or bulking composition of the invention may beprovided as food additive or dietary supplement composition, which maybe administered or ingested at least once daily in unitary dosage form,and in any pharmaceutically acceptable dosage form known or whichbecomes known by those of skill in the art. In addition, the dietarysupplement can be administered by any pharmaceutically acceptable routerecognized by those of skill in the art, for example, oral, enteral,parenteral, intravenous, transdermal, nasal, rectal, topical, vaginal orthe like. In a preferred embodiment, the dietary supplement of theinvention is a unitary dosage form suited for oral administration orconsumption by an individual at least once per day, for example, in acapsule, tablet, caplet, soft gel capsule, controlled release tablet,powder, liquid, liquid or gel filled capsule, and the like.

Additional aspects and advantages of the SAPH compositions which areencompassed by the invention will become evident from the description,non-limiting examples, and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Graphical representation of clinical trial data relating toparticipant response to ingestion of an exemplary SAPH composition ofthe invention (commercially available as PREE™). Participants were askedto rate their responses to PREE™ at each of breakfast, lunch and dinner.

FIG. 2. Graphical representation of clinical trial data relating toparticipant response to ingestion of an exemplary SAPH composition ofthe invention (commercially available as PREE™). Participants were askedto provide an overall combined score for PREE™, in terms of its abilityto reduce meal portions and control hunger at each of the three mealsdaily, combined with an ability to translate these feelings into weightloss. Based on these criteria, participants rated PREE™ as: a) NotEffective: 13.3% of the time; b) Moderately Effective: 45.3% of thetime; and c) Highly Effective: 41.3% of the time.

FIG. 3. Graphical representation of clinical trial data relating toparticipant response to ingestion of an exemplary SAPH composition ofthe invention (commercially available as PREE™). Responding participantswere asked to gauge the degree of their meal portion reduction in termsof the percentage decrease from their regular meal sizes.

FIG. 4. Graphical representation of clinical trial data relating toparticipant response to ingestion of an exemplary SAPH composition ofthe invention (commercially available as PREE™). The incidence ofoccurrence of all study related side effects was recorded.

FIG. 5. Graphical representation of clinical trial data relating toparticipant response to ingestion of an exemplary SAPH composition ofthe invention (commercially available as PREE™). The ability of PREE™ toassist participants in losing weight was measured.

DETAILED DESCRIPTION

The present invention relates to the discovery of surprising andunexpected swelling characteristics of the SAPH compositions of theinvention. As such, the SAPH compositions of the invention areadvantageous and efficacious as dietary supplements or weightloss/weight management compositions. In particular, the compositionsdescribed herein allow for the surprising and unexpectedly beneficialgastric swelling characteristics making them useful as food additives ordietary supplements for the control of food portions, attenuatinghunger, and promoting weight loss and/or facilitating weight management.

As used herein, the terms “super-absorbent polymer hydrogel,” “polymerhydrogel,” “SAPH,” “SAPH material,” “SAPH composition,” “absorbentingestible agent,” “bulking composition,” and “gastric bulking agent”,and combinations thereof, are used interchangeably in reference tocompositions and methods of the invention.

Physiologic control over eating and weight maintenance is highlyredundant. In fact, numerous complex signaling pathways have beenevolutionarily conserved to protect the human body against weightchange—especially weight loss. These compensatory mechanisms areinteractive and overlapping. As a result, dietary and medical methodsdesigned to achieve weight loss have historically delivered poorresults, and even when temporally successful, are difficult to sustain.As such, described herein are compositions and methods useful forregulating and/or suppressing the appetite in an individual. In certainmethods of the invention, compositions of the invention are administeredto or ingested by an individual in unitary dosage form for the reductionof body mass; i.e., body weight.

This application claims the benefit of U.S. Provisional Application Ser.No. 61/026,183 filed Feb. 5, 2008; and U.S. Provisional PatentApplication Ser. No. 61/059,420 filed Jun. 6, 2008; the disclosures ofwhich are hereby incorporated by reference in their entirety.

Several peripheral signaling pathways are known to regulate energyhomeostasis (See Table 1). Insulin and leptin are hormones thatcirculate in proportion to body fat mass and act upon receptors withinthe hypothalamus to reduce appetite. When body fat mass is reducedduring weight loss, insulin and leptin levels decline, stronglystimulating appetite and weight gain. Another controlling hormone,ghrelin, is produced primarily by the gastric epithelium, and appears tostimulate appetite and feeding. Ghrelin levels are inversely related tobody weight, with obese people displaying low ghrelin levels.Diet-induced weight loss has been shown to increase ghrelin levels,implying that ghrelin may play a role in countering such weight loss bystimulating appetite and energy intake.

Ghrelin and is primarily found in the epithelial cells of the stomach,but also in various areas of the brain and hypothalamus. Before eatingthe levels of ghrelin are very high, which stimulates brain cellstelling us that we should eat. After eating, the levels of this hormonedecrease considerably. One of the hormones that counteract the effectsof ghrelin is leptin. Leptin is released by adipose tissue and serves asis the “satiety hormone,” since it provides the hypothalamic neuronalcells with satiation signals. At elevated plasma levels, leptin inducesa sense of satiety, even several hours after food consumption.

Like leptin, the appetite-blocking hormone called obestatin, produced bythe same epithelial cells as ghrelin, also down-regulates hunger. Asobestatin levels increase, receptor signaling to the brain's satietycenter is also increased thus reducing hunger sensation. In addition,food intake is regulated by additional CNS receptors, including themelanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus.The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor,is highly expressed on NPY neurons in the arcuate nucleus, which isaccessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2Ragonist, is released from the gastrointestinal tract postprandially(i.e., after eating a meal) in proportion to the calorie content of ameal which suppresses appetite.

TABLE 1 Summary of Appetite Modifying Hormones Circulating HormonePrimary Action Where Produced Leptin Appetite Suppressant Adipose TissueGhrelin Appetite Stimulant Gastric Epithelium Obestatin AppetiteSuppressant Gastric Epithelium PYY(3-36) Y2R Agonist, AppetiteSuppressant Gastric Epithelium

Historically, ingestible crosslinked polycarboxylic acids have enjoyed awide variety of uses, for example, in the pharmaceutical, food contactand cosmetics industries. However, prior polyacrylates only achievesmall swelling ratios. However, a successful gastric bulking agent willneed to exhibit substantially higher swelling ratios that can occurwithin the gastric environment, preferably at least in excess of 200times gram for gram of water absorption, more preferably at least inexcess of 350 times gram for gram of water absorption, and mostpreferably at least in excess of 500 times gram for gram of waterabsorption.

Adapting a synthetic SAPH material for use as a gastric bulking agentrequires overcoming a number of problems known in the art, including: a)identifying a unified and commercially reasonable combination of anappropriate composition of matter; b) a simple and cost-effective methodof manufacture that will meet regulatory requirements for ingestiblepurposes; c) correct routes of administration; d) ideal deliverymethods, and e) proper dosing regimens, as such are all disclosed in thepresent invention.

Currently available bulking agents, for example, calcium polycarbophil,have proven unsuitable for the present use, i.e., weight loss/appetitecontrol, because the end products swell too little or too slowly to beacceptable as pre-meal gastric bulking agents that are designed to betaken with water prior to meals. For this reason, these materials arecurrently commercialized in ingestible forms as bulk laxatives and havethe laxative effect, which is clearly not considered a desirable sideeffect of the intended purpose of the present invention. Moreover, thecalcium polycarbophil agents have a mild muco-adhesive tendency whichpotentially could interfere with the concomitant ingestion of otherfoods, nutrients, medicants or other products that would reasonably beconsumed by overweight users of the present invention seeking to lose ormanage their weight.

Other issues that have been encountered with prior bulking agentsinclude the excessive presence of undesirable, toxic or carcinogenicby-products or contaminants in SAPH materials which occur during theirmanufacture, i.e., residual solvents (Scheurer focused exclusively onbenzene removal), and by further mention—residual monomers, or residuallow molecular weight oligomers, or residual heavy metals which wouldmake such a material entirely unsuited for the intended use as aningestible product. Furthermore, excess concentrations of unwantedcontaminants are even less desirable due to the relatively large volumesof SAPH materials needed to be ingested to provide for an effectivetemporary pre-meal gastric bulking agent indication.

The present invention offers a number of surprising and unexpectedadvantages over the currently known bulking agents. For example,ingestible material must continuously meet stringent regulatoryrequirements with respect to toxicity, safety, carcinogenicity,manufacturability, purity and environmental standards. In addition, theSAPH material must be approvable by regulatory authorities for use as agastric bulking agent used as a weight loss/weight management tool. Withrespect to the manufacture of hydrogels in general and to SAPHcompositions of the present invention, the selection of: a) rawmaterials for polymerization and cross-linking; b) solvents, and c)manufacturing agents and methods must each be chosen with the endproduct use as an ingestible agent in mind—as has been accomplished bythe present invention. Typically, additional or secondary operationsmust be performed to remove each one of the three classes of unwantedcontaminants in the desired final product: a) residual monomer and lowmolecular weight oligomers; b) residual solvent, or c) residual heavymetal contaminants. However, the invention encompasses a single, unifiedmethodology that encompasses the simultaneous removal of all three formsof undesired impurities to levels sufficiently reduced to meetregulatory scrutiny and thus commercial viability.

Also, the SAPH material must be provided in a conveniently ingestibleform for the stated purpose; i.e. ideally fast-dissolving capsules orgel caps when used as an uncombined weight loss or weight managementtool with a rapidly absorbing SAPH that will adsorb the free waterconcurrently ingested with the capsules or gel caps. Rapid capsuledissolution and SAPH absorption is necessary so that the free water isabsorbed in the stomach by the SAPH prior to its gastric absorption ortransport into the small intestine where it loses its effectiveness forthe purposes of the present invention.

Next, in order to be effective for hunger control/weight management, theSAPH material should provide sufficient volumetric bulking to promote asense of early satiety. In certain embodiments, the volumetric bulkingof the SAPH composition of the invention is at least in excess of 200times gram for gram of water absorption; at least in excess of 350 timesgram for gram of water absorption; or at least in excess of 500 timesgram for gram of water absorption.

In certain embodiments, the SAPH or bulking compositions of theinvention have an average pre-swell particle or grain size of from about100 nm to about 1 mm. The inclusion of some micronized or “fines” of theSAPH materials into a dietary supplement/weight management compositionhas unexpectedly been found to be advantageous for enhancing at leastone of the volumetric bulking and/or rate of swelling. The amount offines, however, must be carefully controlled to avoid unwanted oncoticeffects. In other words, if the weight percentage of the fines is toohigh, a bulk laxative effect may ensue due to the net water inflow intothe gut. Therefore, in certain embodiments, the SAPH or bulkingcompositions of the invention comprise from about 0.5% to about 25% byweight of fines. In any of the embodiments described herein the finesmay have an average pre-swell particle or grain size of from about 0.5microns to about 50 microns. In certain additional embodiments, the SAPHcomposition comprises from about 1% to about 5% by weight of fines. Inany of the embodiments described herein, the fines may have an averagegrain size of from about 1 micron to about 25 microns. In still furtherembodiments, the SAPH compositions of the invention comprise polymerparticles or grains having a plurality of average pre-swell grain sizes.The particular particle size number and distribution will be selecteddepending on a number of considerations including desired volumetricbulking, swelling rate, and/or unitary dosage size. Particles or gainscan be separated on mesh screens of any desired pore size, for example,1 mm, 900 micron, 800 micron, 700 micron, 600 micron, 500 micron, 400micron, 300 micron, 200 micron, 100 micron or less. All mesh sizesoccurring in between the exemplified sizes are expressly contemplated.In certain embodiments the SAPH material of the invention comprises (byweight of total amount of SAPH material) from about 0% to about 5% ofparticles separated on a 850 micron mesh; from about 5% to about 20% ofparticles separated on a 500 micron mesh; from about 25% to about 90% ofparticles separated on a 180 micron mesh; and from about 1% to about 15%of particles separated on a 106 micron mesh; and from about 0.5% toabout 5% of fines having an average size of between about 1 micron and25 microns.

Also, in order to be effective for hunger control/weight management, theSAPH material must be able to provide its action in the gastricenvironment consisting of a unique and widely variable pH, and salinityranges at physiologic temperature. In addition, the SAPH material mustbe non-digestible, so that the hydrogel remains bio-inert throughout itstransit in the body's gastrointestinal tract. Similarly, the body willneed to recognize the SAPH as a particulate in order for the material tobe retained in the gastric lumen for a time that is sufficient for thepurposes of an effective temporary pre-meal gastric bulking agent. Theabove-features are met by one or more embodiments of the SAPHcomposition of the present invention. In certain embodiments, the SAPHcomposition of the invention demonstrates an average swollen particlesize of from about 0.5 mm to 2 mm in the final water-swollen form of theSAPH.

In one or more embodiments of the SAPH composition of the invention, theSAPH material is a water retentive polyelectrolyte hydrogel, not merelya hydrogel sponge, such that the absorbed water will not be releasedduring gastrointestinal transit; neither is it absorbable nor will itabsorb other materials from the gastrointestinal (GI) tract; is toughenough to withstand peristaltic action to remain in a large particlesize to prevent oncotic pressure changes during transit; is able to beeliminated from the GI tract without difficulty and cannot adhere tooral or gastrointestinal linings; is bio-compatible or more preferablybio-inert and remains such during GI transit.

Additional advantages offered by the present invention include one ormore of a) is not an ecological or environmental hazard; b) ismanufacturable at a low cost and easily flowable; especially intoencapsulation embodiments where the potential for degradation oroxidation by other excipients over the course of the product's shelflife must be minimized; c) is fast acting, and d) offers a convenientand non-invasive mechanism of action.

Therefore, in one aspect the invention relates to compositions thatproduce or simulate pre-meal gastric volume in order to promote apre-synaptic mechanical stimulus to gastric receptors. Consumption ofthe compositions of the invention elicit natural physiologic responseswhich govern the release of one or more of these hormonal mediators,timed to decrease the urge to eat and curb the feelings of hunger justprior to, or just upon the initiation of eating. In another aspect, theinvention relates to compositions that, when used regularly over time,induces a progressive physiological modification within these complexsignaling pathways. The result is a modification or override of thenormal energy-management homeostatic responses of the body over time inorder to achieve a sustained state of weight reduction by resetting the“satiety threshold” governed by central nervous system receptorsresponsive to circulating hormones released by gastric sensorymechanisms.

In certain aspects, the SAPH materials of the invention comprise one ormore hydrogel forming polycarboxylic acid compounds formulated for oraladministration to or ingestion by an individual. In any of the SAPH orgastric bulking compositions described herein, the composition cancomprise from about 1% to about 99% by weight of a crosslinkedpolycarboxylic acid. In additional embodiments, the gastric bulkingcomposition comprises from about 10%, or 20%, or 30%, or 40%, or 50% toabout 99% by weight of a crosslinked polycarboxylic acid. The inventionincludes all amounts between the identified ranges. In anotherembodiment, the SAPH material or bulking agent comprises at least one ofa crosslinked homopolymer of polyacrylic acid or polyacrylamide; acrosslinked copolymer of polyacrylic acid and polyacrylamide; the alkalimetal salts of these materials or a combination thereof.

In any of the embodiments described herein, the polymers of the SAPHmaterial can be prepared from one or more ethylenically unsaturatedcarboxylic acids; ethylenically unsaturated carboxylic acid anhydrides,or acid or basic salts thereof. Additionally, the polymers may includecomonomers, which are known in the art, for grafting onto the SAPHmaterials including comonomers such as an acrylamide, an acrylonitrile,a vinyl pyrrolidone, a vinyl sulphonic acid or a salt thereof, acellulosic monomer, a modified cellulosic monomer, a polyvinyl alcoholor a starch hydrolyzate. In certain embodiments the SAPH material of theinvention includes a comonomer comprising greater than about 5 percentby weigh of the monomer mixture. In other embodiments, the SAPH materialincludes a comonomer comprising greater than about 10 percent by weightof the monomer mixture. In other embodiments, the SAPH material of theinvention includes a comonomer comprising about 25 percent by weight ofthe monomer mixture.

In any of the embodiments described herein, the unsaturated carboxylicacid and carboxylic acid anhydride monomers may include at least one ofan acrylic acid such as, for example, but without limitation, acrylicacid, methacrylic acid and ethacrylic acid. In other embodiments,grafted or copolymer examples may include the use of acrylamide, anacrylonitrile, a vinyl pyrrolidone, a vinyl sulphonic acid or a saltthereof, a cellulosic monomer, a modified cellulosic monomer, apolyvinyl alcohol or a starch hydrolyzate can be selected. In anembodiment, the starting monomer is acrylic acid, methacrylic acid, or asalt thereof, for example, a sodium salt of acrylic acid.

In certain aspects, the SAPH material of the invention further includesat least one of a (poly)vinyl or non-vinyl crosslinker. Many vinylcompounds having at least two polymerizable double bonds that can act ascross-linkers for the SAPH of the present invention are known, andinclude, for example, i) non-vinyl crosslinkers: agents having at leasttwo functional groups capable of reacting with the carboxyl groups ofthe polymer, such as glycerin, polyglycols, ethylene glycol, digylcidylether, and aliamines. Additional, examples of these compounds are givenin U.S. Pat. Nos. 4,666,983; 5,145,906; and 4,734,478; the disclosure ofwhich are incorporated herein by reference in their entirety.

In an additional aspect, the invention encompasses methods of producingSAPH materials. In certain embodiments, the methods of invention includeadding the non-vinyl cross-linkers homogeneously to the polymerizationmixture at the start of the process prior to introduction of a fluidsolvent. In any of the embodiments described herein, the non-vinylcrosslinker includes at least one of hexane diamine, glycerin, ethyleneglycol diglycidyl ether, ethylene glycol diacetate, polyethylene glycol400, polyethylene glycol 600, polyethylene glycol 1000 or combinationsthereof. In another embodiment, the non-vinyl crosslinker comprises atleast one of polyethylene glycol 400, polyethylene glycol 600 or otherPEG material listed as generally recognized as safe or as may beotherwise approvable by the FDA or such similar regulatory authoritiesas acceptable for human ingestion applications.

The total amount of all crosslinkers present must be sufficient toprovide a SAPH material with good absorptive capacity, good absorptionunder load, and high yields of the desired SAPH materials with extremelylow concentrations of extractable materials from the final reactionproduct; including extremely low concentrations of residual monomers,low molecular weight oligomers, solvents and or other volatile organicmaterial. As described herein, it is desirable that the monomers,comonomers, crosslinkers, etc., of the SAPH be preferentially soluble inthe supercritical carbon dioxide phase of the preferred manufacturingmethod of the present invention, whereas the polymer and hydrogel willnot be soluble. For lightly crosslinked applications, the crosslinkersmay be present in an amount of at least about 500 parts per million;about 2500 parts per million; or about 5000 parts per million by weightbased on the amount of the polymerizable monomer present. For moreheavily cross-linked applications, the crosslinkers may be present in anamount of about 50,000 parts per million or less by weight; about 25,000parts per million or less by weight; or about 10,000 parts per millionor less by weight based upon the amount of the polymerizable monomerpresent.

In those embodiments of the present invention that utilize a blend of(poly)vinyl crosslinkers with non-vinyl and or dimodal crosslinkers, thesolvation of all three types of crosslinkers is additive in nature. Thatis, if the amount of one crosslinker is increased the amount of anothermust be decreased to maintain the same overall solvation in thesupercritical fluid phase. In addition, the proportion of thecrosslinker components within the blend may be varied to achievedifferent SAPH properties and processing characteristics. This isespecially important for an ingestible material that is to have itsaction occur within the gastric environment. If too little of the totalcrosslinker blend is composed of polyvinyl crosslinker the polymerizedhydrogel may not have sufficient toughness to be easily ground,processed, and dried. For this reason the proportion of polyvinylcrosslinker in the total crosslinker blend is preferably at leastsufficient to produce a hydrogel that has enough toughness to be readilyground, processed, and dried. This toughness is inversely proportionalto the centrifuge capacity of the SAPH material after drying but beforeheat-treatment. The exact amount of crosslinker required in the blend toachieve this level of toughness will vary, depending on the preferredfinal intended use of the SAPH material.

Depending upon the swelling ratio of the SAPH used, practical volumes ofingested SAPH of the present invention in non-combination formats andsome combination formats, would preferably be at least 250 milligramsper dose, more preferably be at least 500 milligrams per dose, and mostpreferably be at least 750 milligrams per dose, given with 6 to 12 ozwater 30 to 60 minutes before meals.

An additional aspect the invention relates to methods for controllingappetite in an individual comprising administering or consuming aneffective amount of a SAPH composition of the invention in a unitarydose, wherein the SAPH is effective for controlling appetite. In anotherembodiment the invention comprises a method for reducing weight in anindividual comprising administering or ingesting an effective amount ofthe SAPH composition of the invention in a unitary dosage form as atemporary pre-meal gastric bulking agent to suppress appetite, andtherefore, assist in weight loss and/or weight management and/or promotea feeling of early satiety in an individual. In still other aspects theinvention relates to methods for reducing caloric intake in anindividual comprising administering to or ingestion by an individual orconsuming an effective amount of the polycarboxylate composition of theinvention.

An “effective amount”, “effective dose”, “therapeutically effectiveamount”, or “pharmaceutically effective amount” is that dose required toprevent, inhibit the occurrence, treat (alleviate a symptom to someextent, preferably all of the symptoms) or cause or promote the desiredphysiological change in an organism. The effective amount depends on thetype of condition or disease, the composition used, the route ofadministration, the type of mammal being treated, the physicalcharacteristics of the specific mammal under consideration, concurrentmedication, and other factors which those skilled in the medical artswill recognize. Generally, an amount between 0.1 mg/kg and 1000 mg/kgbody weight/day of claimed ingredients is administered/ingesteddepending upon the potency of the SAPH. In addition, effective amountsof the compositions of the invention encompass those amounts utilized inthe examples to facilitate the intended or desired biological effect.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50.

In any of the aspects or embodiments described herein, an effectiveamount of the dietary supplement composition of the present inventionmay be administered or ingested at least once daily, and in anypharmaceutically acceptable dosage form known or which becomes known bythose of skill in the art. In addition, the SAPH may be provided as afood additive or dietary supplement which can be administered by anypharmaceutically acceptable route recognized by those of skill in theart, for example, oral, enteral, parenteral, intravenous, transdermal,nasal, rectal, topical, vaginal or the like. In a preferred embodiment,the SAPH is provided as a food additive or dietary supplement of theinvention and is a unitary dosage form suited for oral administration orconsumption by an individual at least once per day, for example, in acapsule, tablet, caplet, soft gel capsule, controlled release tablet,powder, liquid, liquid or gel filled capsule, and the like.

In any embodiment described herein, the compositions of the inventioncan be administered together with any number of pharmaceuticallyacceptable excipients. In any of the SAPH or bulking compositionembodiments described herein, the composition may contain from about0.01% to about 80% by weight of an excipient. In certain embodiments,the SAPH or bulking agent compositions comprise from about 0.01% toabout 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 50%, or60%, or 70% by weight of an excipient. The invention contemplates allamounts occurring between the identified ranges. One or morecompositions of the invention can be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants, and if desired other active ingredients. Thepharmaceutical compositions of the invention can be in a form suitablefor oral use, for example, as tablets, troches, lozenges, aqueous oroily suspensions, dispersible powders or granules, emulsion, hard orsoft capsules, or syrups or elixirs.

In any of the preferred embodiments the composition of the inventionalso comprises at least one of the following: a stabilizer or carrier,for example, cellulose, magnesium stearate, silica; a lipid; an oil; asalt; an acid; a base; an emulsifier; an excipient; a flavoring agent;or combinations thereof. The inert matrix of the present inventioncomprises at least one of the following: cellulose fiber (as BH 200),magnesium (as magnesium stearate), and silica. In certain embodiments,the composition of the invention comprises from about 0.01 mg to about1000 mg of cellulose fiber. In other embodiments, the composition of theinvention comprises from about 0.01 mg to about 1000 mg of L-Leucine.

Compositions intended for oral use can be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more suchsweetening agents, flavoring agents, coloring agents or preservativeagents in order to provide pharmaceutically elegant and palatablepreparations. Capsules, tablets or gel caps contain the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipients that are suitable for the manufacture of capsules, tablets orgel caps (i.e., soft gel capsules). These excipients can be for example,diluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for exampleL-Leucine, magnesium stearate, stearic acid or talc.

In certain embodiments, the SAPH or bulking composition comprises fromabout 0.01% to about 20.00% by weight of stearic acid. In additionalembodiments the SAPH or bulking composition comprises from about 0.01%to about 10.00% by weight of magnesium stearate. In still additionalembodiments, the SAPH or bulking composition comprises from about 0.01%to about 20.00% by weight of magnesium silicate (i.e., talc).

Hydrophobic excipients, for example, surfactants, emulsifiers, lipids,detergents, lubricants, etc. . . . can, in some instances, delay therate of SAPH or bulking composition swelling. Therefore, the inventionalso contemplates embodiments in which the excipients are hydrophilic.It is believed that hydrophilic excipients allow for the more rapidfluid absorption of the SAPH hydrogel (i.e., allows faster swelling)within the gastric environment. Accordingly, in certain additionalembodiments, the SAPH or bulking composition comprises a hydrophilicexcipients, for example, an amino acid excipient, such as for example,Leucine, or L-Leucine.

Leucine (abbreviated as Leu or L) is an •-amino acid with the chemicalformula HO₂CCH(NH₂)CH₂CH(CH₃)₂. It is an essential amino acid, whichmeans that humans cannot synthesize it. With a hydrocarbon side chain,leucine is classified as a hydrophobic amino acid. It has an isobutyl Rgroup. Leucine is a major component of the sub units in ferritin,astacin and other ‘buffer’ proteins. As an essential amino acid, leucineis not synthesized in animals, hence it must be ingested, usually as acomponent of proteins. It is synthesized in plants and microorganismsvia several steps starting from pyruvic acid. Leucine has been found toslow the degradation of muscle tissue by increasing the synthesis ofmuscle proteins. Leucine is utilized in the liver, adipose tissue, andmuscle tissue. In adipose and muscle tissue, leucine is used in theformation of sterols, and the combined usage of leucine in these twotissues is seven times greater than its use in the liver. As a foodadditive L-Leucine has E number E641 and is classified as a flavorenhancer. In studies in which Leucine was injected directly into thebrains of rats, the appetite of the rats was reduced. Evidences fromseveral studies, on rats, suggest that leucine is involved in proteinsynthesis in the skeletal muscle, and slows muscle degradation. Inaddition, Leucine is rapidly soluble in aqueous environments such asthose that exist in the stomach. In particular, micronized Leucine is aknown dietary supplement taken by body builders to improve muscledevelopment, and is almost instantly soluble in water. MicronizedLeucine is a powder that demonstrates a smooth or “slick” feel to thetouch, and can behave similarly to a lubricant in the formulation of thecomposition of the invention.

The addition of Leucine in the SAPH or bulking compositions of theinvention results in surprising and unexpected synergism when formulatedand administered with the compositions of the present invention becauseit allows for faster swelling of the polymer hydrogel, and furtherenhances appetite modulation and muscle mass. Additional advantages ofusing Leucine include its low cost, availability, safety and GRAS statusas a food additive, and purity. In particular, the use of micronizedL-Leucine is readily available and is amenable for use in theformulations of the present invention. In any of the embodimentsdescribed herein, the SAPH or bulking compositions of the inventioncomprises from about 0.5% to about 50% of at least one of Leucine, orL-leucine, or micronized L-leucine, or a combination thereof. In certainadditional embodiments, the SAPH or bulking composition of the inventioncomprises from about 1% to about 15% of at least one of Leucine, orL-leucine, or micronized L-leucine, or a combination thereof. In anadditional embodiment, the SAPH or bulking composition of the inventioncomprises about 5% of at least one of Leucine, or L-leucine, ormicronized L-leucine, or a combination thereof.

The capsules, tablets or gel caps can be uncoated or they can be coatedby known techniques. In some cases such coatings can be prepared byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as hard gelatin capsuleswherein the effective ingredient is mixed with an excipient or inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin or olive oil. In addition, in any of the embodiments thecomposition of the invention may further comprise a diluent, or otheradditive, such as binders, fillers, supports, thickening agents,flavoring agents, gums, coloring agents, preservatives, stabilizers,regulators, emulsifiers, flow agents, lubricants, absorbents, and thelike or combinations thereof. In still another embodiment, thecomposition of the invention may comprise a dietary fiber supplement,for example cellulose, glucomannan, oat bran or other natural fibersource. The present invention includes compositions prepared for storageor administration which include a pharmaceutically effective amount ofthe desired compounds in a pharmaceutically acceptable carrier ordiluent. Acceptable carriers or diluents for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985) hereby incorporated by reference herein. For example,preservatives, stabilizers, dyes and flavoring agents can be provided.These include sodium benzoate, sorbic acid and esters ofp-hydroxybenzoic acid. In addition, antioxidants and suspending agentscan be used.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents can be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions can also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin or other natural sweeteners like Stevia®.

Oily suspensions can be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions can contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents can beadded to provide palatable oral preparations. These compositions can bepreserved by the addition of an anti-oxidant such as ascorbic acid oralpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, can also be present. Pharmaceutical compositions of theinvention can also be in the form of oil-in-water emulsions. The oilyphase can be a vegetable oil or a mineral oil or mixtures of these.Suitable emulsifying agents can be naturally-occurring gums, for examplegum acacia or gum tragacanth, naturally-occurring phosphatides, forexample soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol, anhydrides, for example sorbitan monooleate,and condensation products of the said partial esters with ethyleneoxide, for example polyoxyethylene sorbitan monooleate. The emulsionscan also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations can also contain a demulcent, as well as preservative andflavoring and coloring agents. The pharmaceutical compositions can be inthe form of a sterile injectable aqueous or oleaginous suspension. Thissuspension can be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilcan be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Beginning with U.S. Pat. No. 2,649,439 issued to Brown in August 1953,numerous examples in the prior art, as extensively disclosed by theapplicant above, have described the manufacture of SAPH polymericmaterials. Brandt in U.S. Pat. Nos. 4,654,039 and Re. 32,649, disclosesa process for the preparation of SAPH resins and the use of knowncrosslinking agents for such materials. A variation of the basic processis taught in GB Patent 2,119,384, which discloses a post-polymerizationsurface crosslinking process in which the previously polymerizedabsorbent resin powder is mixed with crosslinkers, preferablypolyalcohols, a solvent and water, to coat the resin surface, and heatedto temperatures in the range of 90 to 300° C. to crosslink the surface.U.S. Pat. No. 5,506,324 discloses polymeric resin particles comprisingpolymers containing carboxyl moieties which are crosslinked using C2-10polyhydric hydrocarbons which are ethoxylated with from 2 to 8 ethyleneoxide units per hydroxyl moiety of the ethylene oxide chain wherein thehydroxyl moiety at the end of each chain is esterified with a C2-10unsaturated carboxylic acid or ester thereof. In a preferred embodiment,the SAPH resin particles are subjected to heat-treatment after dryingand sizing.

Numerous other examples of similar approaches to the manufacture of SAPHmaterials are cited in the prior art. However, each is plagued with theproblem of having the presence of excessive amounts of impurities in theform of residual heavy metals, and or residual monomers, and or residuallow molecular weight oligomers, and or residual solvents; which renderthe final material too toxic, too carcinogenic or otherwise unacceptableby regulators for human ingestion and consumption in the anticipatedamounts necessary to construct a suitable SAPH as required by thepresent invention.

Accordingly, it is desirable to have a process for preparing a SAPHmaterial with reduced residual monomer and low molecular weightoligomers concentrations; reduced residual solvent concentrations; andreduced heavy metal concentrations which would not be toxic orcarcinogenic and would be scientifically and medically acceptable forhuman ingestion and consumption within the recommended dosage range fora SAPH material sued for the purposes of providing temporary, pre-mealgastric bulking to assist in appetite suppression and weight management.

Therefore, in another aspect, the present invention relates to a processby which a SAPH material can be manufactured such that it has: a) lowresidual monomer and low molecular weight oligomer concentrations; andb) low residual solvent concentrations, including low residual organicvolatiles concentrations, and c) low heavy metal concentrations wherebythe final material is non-toxic, non-carcinogenic and acceptable byregulators for human ingestion and consumption for the purposes ofproviding temporary, pre-meal gastric bulking to assist in appetitesuppression and weight management.

In an embodiment of this aspect of the invention, the process comprises(i) polymerizing a monomer or a monomer mixture in a polymerizationmixture comprising: (a) one or more ethylenically unsaturatedcarboxyl-containing monomers, (b) one or more crosslinking agents, and(c) a polymerization medium consisting of a supercritical fluid solvent,to form a crosslinked hydrogel, (ii) venting the supercritical fluidsolvent which contains undesirable or excessive concentrations ofreaction products, (iii) comminuting the hydrogel to resinous particles(iv) drying the hydrogel to form resinous crystals, (v) mesh sorting theresinous crystals to a preferred particle size; and (vi) heat treatingthe resinous crystals.

In certain embodiments, the SAPH material produced according to themethods of the invention comprises a cumulative residual monomer and lowmolecular weight oligomer content of less than about 50 ppm; less thanabout 10 ppm; and/or less than about 2 ppm, based on the weight of thesolid polymer. The residual amounts are significantly less than theregulatory standards imposed for maximum concentrations of any suchparticular monomers as are regulated for daily expose limits as used inthe embodiments of the present invention.

In certain embodiments, the SAPH material produced according to themethods of the invention comprises a residual organic volatiles and orsolvents content less than about 50 ppm; less than about 10 ppm; and/orless than about 1 ppm, based on the weight of the solid polymer. Theresidual amounts will be significantly less than the regulatorystandards imposed for maximum concentrations of any such particularsolvents or organic volatiles as are regulated for daily expose limitsas used in the preferred embodiments of the present invention.

In certain embodiments, the SAPH material produced according to themethods of the invention comprises a residual heavy metals content lessthan about 10 ppm; less than about 5 ppm; and/or less than about 1 ppm,based on the weight of the solid polymer. The residual amounts will besignificantly less than the regulatory standards imposed for maximumconcentrations of any such particular metals as are regulated for dailyexpose limits as used in the preferred embodiments of the presentinvention.

Various processes have been used to attempt removal of unwantedmanufacturing by-products and toxic contaminants from SAP materials. Forexample, in the past fluid bed dryers have been used to reduce residualsolvent. Unfortunately, these methods are unable to reduce residualsolvents to below about 10 ppm and such drying methods can take severaldays to eliminate enough residual solvent to meet current regulatorymandates. In addition, drying methods are both expensive andtime-consuming. Furthermore, drying methods are only useful for volatilematerials and are not capable of eliminating non-volatile materials inthe form of either residual monomers, low molecular weight oligomers ortoxic heavy metals; and thus the exclusive use of drying methods wouldbe precluded as an appropriate choice for manufacturing a SAPH into anacceptable ingestible form.

Second, azeotropic distillation (AD) techniques have been variouslydescribed and are well known to those skilled in the art. AD is used toremove organic solvents from aqueous suspensions of polymers. However,the AD process functions only if the organic solvent has a certaindegree of water-solubility, which is frequently not the case whenpurifying SAPH materials where the solvents are trapped within theporous domains of the cross-linked hydrogel matrix material. Ofsignificance, AD techniques are also not useful in removing unwantedresidual monomers, low molecular weight oligomers or heavy metals.Therefore, AD methods would not be suitable for removing the unwantedcontaminants found in commercially available SAP materials as isrequired for the preferred use of this invention.

Third, organic solvents can be extracted by other organic solvents. Ifthe extractant is not water-soluble, it in turn has to be removed in anadditional step. If it is water-soluble, it can be removed by washingthe material with water. However, the by-product is large amounts ofcontaminated wastewater that has to be removed, which increases processcosts significantly. Furthermore, AD does nothing to remove unwantedresidual monomers low molecular weight oligomers, or heavy metals.

Fourth, organic solvents can also be removed via steam-treatment.However, the use of steam poses technical problems because the intensivethermal stress of the steam can collapse the pore structure of the SAPHmaterial if the softening point of the polymer network is exceeded.

Fifth, supercritical fluid extraction (SFE) methods and its variantshave been applied as a separate step in polymer purification and suchmethods are disclosed in the prior art. However, of importance to thisinvention, no prior art disclosure provides for the use of asupercritical fluid medium being incorporated as the organic phasesolvation step in the manufacture of SAPH materials, especially as suchpertains to the intended use herein. The cost-savings advantages,product yield, and simplicity of the method disclosed in this presentinvention provide compelling improvements and inventive advancements inthe art of manufacturing ultra-pure SAPH materials.

Sixth, European Patent Publication 505 163 relates to a method ofreducing residual (meth)acrylic acid present in polyacrylic acid SAPHgel polymers that comprises treating the polymers with a combination ofa surfactant having a certain HLB and a vinyl addition compound that canreact with a vinylic double bond. Examples of the vinyl additioncompound include sulfites and bisulfites. However, this method does notremove excess solvents or heavy metals.

U.S. Pat. No. 5,629,377 discloses SAPH materials with high absorptionvalues and low residual monomer levels. The material is prepared bypolymerizing unsaturated carboxyl containing monomers in the presence ofa chlorine or bromine-containing oxidizing agent to form a hydrogel thatis then heated to a temperature preferably from 210° C. to 235° C.Although the method is effective for improving absorbency, the high heattreat temperature needed to activate the chlorine or bromine-containingoxidizing agent is detrimental for various reasons, including energycost and loss of moisture. Neither does the process reduce residualsolvent or other volatile concentrations to acceptable levels.

U.S. Pat. No. 6,914,099 discloses SAPH polymers having reduced levels ofresidual monomer produced using a peroxodisulfate salt additive in themanufacturing process. Such additive is toxic, expensive and does notremove low molecular weight oligomers, residual solvents or heavymetals. Rebre, et. al. in U.S. Pat. Nos. 5,373,066, 5,408,006,5,442,014, and 5,563,218 discloses water absorbent polymers havingreduced levels of residual monomer produced using hydrogen peroxide asan additive in the manufacturing process. Similarly, such disclosuresfail to describe a reduction of solvents and other volatiles, and heavymetals to acceptable levels for the purposes described herein.

Additional aspects and embodiments will be evident to the skilledartisans from a review of the appended non-limiting examples. Theaccompanying examples, which are incorporated into and form a part ofthe specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The examples are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention.

Exemplary Polymerization Method of SAPH Materials:

The present invention discloses the use of a supercritical fluidenvironment in order to form the solvent of choice for thepolymerization medium. The choice of the polymerization medium and theselection of a supercritical solvent would be beneficial where themonomers and other starting raw materials and manufacturing materialsare soluble in said solvent and the desired final polymers areinsoluble. In addition, the supercritical solvent must be inert to themonomers and the polymers, and will preferably have the same solvationcharacteristics as an aromatic or aliphatic hydrocarbon or ahalohydrocarbon as are typically used in the organic phase of suchpolymerization reactions well known in the prior art.

Although those skilled in the art will recognize that othersupercritical fluids would be effective for the uses described herein,the most preferable supercritical fluid polymerization medium of thepresent invention will be comprised of carbon dioxide (CO₂). CO₂ ischaracterized as a non-polar solvent with solubility parameters similarto hexane. It does, however, have some affinity with slightly polarmolecules because of its molecular quadrupole. Carbon dioxide is alsoselected as the most preferred solvent in the supercritical fluid methoddisclosed herein due to its convenient critical temperature (31.3° C.)and pressure (7.4 MPa), low cost, low toxicity, ease of distillation andrecycling, and non-explosive character.

Those skilled in the art will recognize that the use of a supercriticalfluid as the solvent in the polymerization medium may be furtherenhanced by the addition of other liquid or liquefiable solvents to thereaction chamber. These solvents called, modifiers, can be added to thesupercritical carbon dioxide medium as well in order to increasesolubility or enhance displacement of the desired extractants from theSAPH matrix while still confined in the pressurized reaction container.Common modifiers useful in the methods of the invention includemethanol, benzene, hexane, chloroform and others. It is desirable thatthe selected modifier act by swelling the polymer to increase diffusionand extraction rates as well as having appropriate levels ofacceptability as an ingestible material at the reduced residual levelsmade available by the present invention. Modifiers useful in the methodsof the invention include non-polar or aromatic as well as polar.Therefore, it is desirable that the modifier selected will enhanceextraction even when solubility is not a limiting factor. It is alsodesirable that the selected modifiers be ingestible and non-toxic, andotherwise acceptable by regulatory authorities for the disclosedintended use of this present invention. In certain embodiments of themethod of the invention, the modifier comprises at least one ofcyclohexane, hexane, methanol, or a combination thereof. Methanol isuseful because of its low toxicity and ability to cause significantswelling in the SAPH materials of the present invention in thesupercritical phase, its volatility upon distillation, and easyrecycling in the manufacturing process.

In addition to the incorporation of modifiers, those skilled in the artwill recognize that the concomitant use of ultrasound or microwaveheating methods as are disclosed in the prior art may further improvethe efficiency of the purification of the SAPH matrix.

Typically the polymerization phase of the manufacturing process for SAPHmaterials involves the introduction of a free radical or oxidationreduction (redox) catalyst system usually a chlorine- orbromine-containing oxidizing agent under conditions such that acrosslinked hydrophilic material is prepared. The free radical initiatormay be any conventional water soluble free radical polymerizationinitiator including, for example, peroxygen compounds such as sodium,potassium and ammonium persulfates, caprylyl peroxide, benzoyl peroxide,hydrogen peroxide, cumene hydroperoxide, tertiary butyl diperphthalate,tertiary butyl perbenzoate, sodium peracetate and sodium percarbonate.In certain embodiments of the method of the invention, the redoxcatalyst is hydrogen peroxide, which has low ingestible toxicity.

Conventional redox initiator systems can also be utilized. These systemscan be formed by combining the foregoing peroxygen compounds withreducing agents, such as, for example, sodium bisulfite, sodiumthiosulphate, L- or iso-ascorbic acid or a salt thereof, or ferroussalts. In certain embodiments, about 5 mole percent or less of theinitiator can be employed, based on the total moles of polymerizablemonomer present. In other embodiments, from about 0.001 to about 0.25mole percent; or from about 0.25 to about 1.0 mole percent of initiatoris employed, based on the total moles of polymerizable monomer to bepolymerized in the supercritical fluid medium. In certain embodiments ofthe invention, the reducing agent is sodium bisulfate, which has lowingestible toxicity.

In one embodiment wherein the dried hydrogel is subjected toheat-treatment, the process may be conducted in the presence of achlorine- or bromine-containing oxidizing agent. The selection of thechlorine- or bromine-containing oxidizing agent if used will need to becompatible with the acceptable ingestion criteria as stated herein. Thechlorine- or bromine-containing oxidizing agent is present in an amountsuch that after heat-treatment the desired balance of resin propertiesis achieved. In certain embodiments, the method comprises including atleast about 10 ppm by weight of a chlorine- or bromine-containingoxidizing agent, based on the total weight of monomers; at least about50 ppm; at least about 100 ppm; or at least about 200 ppm. It isdesirable that the amount of a chlorine- or bromine-containing oxidizingagent employed is about 2000 ppm or less by weight based on the totalweight of monomers present; is about 1000 ppm or less; is about 800 ppmor less; or is about 500 ppm or less. The chlorine- orbromine-containing oxidizing agent is preferably dissolved or dispersedin the polymerization mixture prior to initiation of the polymerization.However, it may also be applied as an aqueous solution to the hydrogel.

Modified Method of Inverse Suspension Polymerization

The SAPH materials of the present invention such as crosslinkedpoly(acrylic acid) can be synthesized by inverse suspensionpolymerization techniques modified to accept a supercritical fluidsubstituted for the organic phase solvent. In one embodiment of thismethod of the invention an aqueous phase containing a preferredpartially neutralized acrylic acid, a crosslinking agent, and aninitiator agent are dispersed in the supercritical fluid phase andstabilized by a surfactant. The inverse suspension can be carried outusing supercritical CO₂ as the organic phase solvent. In an embodiment,the polymerization can be initiated by sodium or potassium persulfatewith PEG 400 or PEG 600 as the preferred crosslinkers, using methanol asthe modifier, and using sorbitan monooleate as the surfactant. Incertain embodiments, the degree of neutralization of the monomer is fromabout 25% to about 50%; or about 75%.

In an embodiment of this method of the invention, the process isperformed in a batch manner wherein all of the reaction materials arecontacted and the reaction proceeds with the intermittent or continuousaddition of one or more of the components, including the supercriticalCO₂ fluid acting as the solvent is either pulsed intermittently orcontinuously cycled through the polymerization medium for thesynchronous and or simultaneous removal of solubilzed and or suspendedby-products, contaminants and other unwanted residuals targeted forremoval. During the reaction period the polymerization mixture iscontinuously subjected to polymerization conditions that are sufficientto produce the SAPH's resinous particles in ultra-pure form by theventing, distilling and recycling the CO₂ in order to continuouslyremove any of the undesirable contaminants and excessive concentrationsof unused raw materials and undesirable reaction by-products.

Traditional inverse suspension polymerization procedures as described ingreater detail in Obayashi et al., U.S. Pat. No. 4,340,706, and inFlesher et al., U.S. Pat. No. 4,506,052, allow for the addition of otheringredients such as surfactants, emulsifiers and polymerizationstabilizers, however, when employing organic solvents, as is necessaryto form the SAPH materials of this invention, these traditional methodsrequire that the hydrogel-forming polymer material is recovered fromsuch processes and is separately treated to remove substantially all ofthe excess organic solvent, heavy metals and residual monomer and lowmolecular weight oligomers. Furthermore, such materials generally absorbthe entire aqueous reaction medium during the process requiring: 1)shaping by an agitator; 2) recovery from the reaction medium byazeotropic distillation and/or filtration followed by drying. Ifrecovered by filtration, then some means of removing the solvent presentin the hydrogel must be used. Such means are commonly known in the art.These additional steps are obviated by the present invention's use ofsupercritical fluid reactions most preferably using CO₂ or othersuitable material.

Reaction Temperature—Cycling Method:

Poly(acrylic acid), as a SAPH material encompassed by the presentinvention has a relatively high glass transition temperature ofapproximately 102° C. Its manufacture may be performed at anytemperature at which polymerization occurs recognizing that undersupercritical fluid conditions, the glass transition temperature may bedepressed. The supercritical phase requires an environment of increasedpressures sufficient for maintenance of the supercritical phase. Thetemperatures must be elevated as well; preferably to at least about 25°C.; at least about 50° C.; or at least about 75° C. However, under themethod of the present invention, the polymerization medium isintermittently spiked to a temperature that is simultaneously: a) belowthe apparent glass transition temperature of the SAPH material beingproduced under supercritical conditions, and b) above the boiling pointsof the preferred solvents, surfactants and modifiers added, and c) abovethe solvation temperature and melting point of the monomer(s) targetedfor reaction and subsequent removal.

An additional benefit of the use of supercritical environment of thepresent invention allows for a reduction of the optimum operatingtemperature of the polymerization reaction. The supercriticalenvironment not only improves polymerization efficiency, and reactionyields; the temperature lowering substantially lowers manufacturingcosts and saves energy.

Reaction Pressure—Cycling Method:

The reaction may be performed at any pressure above carbon dioxide'ssupercritical fluid pressure (7.4 MPa) and at which polymerizationoccurs. In certain embodiments of the method of the invention thereaction is performed at a pressure of at least about 10 MPa; at leastabout 15 MPa; or at least about 25 MPa. However, in no case will thereaction pressure be of sufficient magnitude to reduce reaction yields,as for example by lowering the reaction temperature to a sub-thresholdglass transition point that would effect efficient polymerization. Inanother embodiment, the process utilizes pressure cycling to reduce andincrease temperatures within the reaction container. Adding a recycledpurified distillate charge of CO₂ under pressure controllably increasesthe reaction temperature and provides a solvent medium free of targetedresiduals, thus driving the equilibrium toward a maximally rapid uptakeof newly formed solvate from the polymerization medium. Venting thesupercritical CO₂ controllably promotes a temperature decline within thereaction container. Thus the synchronous cycling of pressures,temperatures, newly introduced charges of CO₂ and reaction materialsallows for a maximally efficient polymerization/solvation environmentwhile simultaneously maximally removing unwanted impurities and targetedcontaminants resulting in ultra-pure SAPH materials of the presentinvention.

Reaction Time:

The reaction is conducted for a time sufficient to result in the desiredconversion of monomer to crosslinked hydrophilic resin. Preferably, theconversion is at least about 95 percent; at least about 98 percent; orat least 99.99 percent. A diminishing returns cost analysis is essentialto determine the overall time requirements based upon the desired purityand throughput for the commercial manufacturing of the SAPH material. Incertain embodiments the maximum reaction time is not more than about 6hours; not more than about 3 hours; or not more than about 1 hour.

Neutralization:

In any of the embodiments of the process described herein, at leastabout 25 mole percent; at least about 50 mole percent; or at least about65 mole percent of the carboxylic acid units of the SAPH material areneutralized with base. This neutralization may be performed before orafter completion of the polymerization. In an embodiment the startingmonomer mix has carboxylic acid moieties which are neutralized to thedesired level prior to polymerization. The final polymer or the startingmonomers may be neutralized by contacting them with a salt-formingcation. In any of the embodiments described herein, the salt-formingcations include: an alkaline metal; ammonium, substituted ammonium, oramine based cations; an alkali metal hydroxide such as, for example,sodium hydroxide or potassium hydroxide, or an alkali metal carbonatesuch as, for example, sodium carbonate or potassium carbonate. In stillanother embodiment, the starting monomers are neutralized with sodiumhydroxide to 75 mole percent.

Fine Spiking Method:

It is also possible to prepare the SAPH of the present invention byadding recycled “fines” to the polymerization mixture. “Fines” aregenerally considered to include, but are not limited to, the fraction ofSAPH resin particle that passes through a 140 mesh screen when the driedand ground product is screened prior to heat-treatment. The amount offines added to the polymerization mixture is, on a total solids basis,preferably less than about 12 weight percent; less than about 10 weightpercent; or less than about 8 weight percent. This method improves thereaction yields and reduces manufacturing losses of the resins made andconcomitantly reduces the costs of manufacture of the final SAPHmaterial.

Method of Comminution:

After removal from the reactor, the SAPH material is subjected tocomminution by a convenient mechanical means of particle size reduction,such as grinding, chopping, cutting or extrusion as are commonlyemployed by those skilled in the art. The size of the final particlesafter particle size reduction should be such that homogeneous drying ofthe particles can occur. Depending upon the intended use of the SAPH ofthe present invention, desired particle sizes will range from a smallestconvenient size of approximately 100 to 250 microns for the finestpowders, used for example as in some mixes and nutrition bars; up to alargest convenient size of approximately 750 to 1,000 microns for use incertain puddings. Therefore, the preferred particle sizes of the undriedmaterial range from 0.05 to 0.5 mm, or other such size as will providefine resinous crystals or powders of a desired particle size upondrying. This particle size reduction can be performed by any means knownin the art that gives the desired result. Preferably, the particle sizereduction is accomplished by chopping. Most preferably, the particlesize reduction is accomplished by grinding. Final size selection isaccomplished by serial mesh screening techniques as are well known inthe art, with “fines” collected for reuse as described above. It isdesirable to reduce the amount of fine powder form in the final SAPH mixto reduce the inhalable dust used in further processing into capsules orother products as an occupational safety and environmental safety factorfor the workers who would potentially be exposed to such dusts.

Exemplary Heat Treatment Method:

In order to improve the swelling efficiency of high molecular weightcrosslinked polycarboxylic acids, crosslinked SAPH materials aretraditionally subjected to heat treatment. These SAPH materials, in theform of the suspension obtained in the polymerization, can be treated atfrom 80 to 130° C. Traditionally, if the polymerization has been carriedout using a suspending agent whose boiling point is above 80° C., thepolymer suspension is heated in an autoclave under superatmosphericpressure. However, this separate step is obviated by the presentinvention where the polymerization is conducted under supercriticalconditions and is a benefit thereof. During the heating of the SAPH ofthe present invention, the SAPH is slowly isolated as a solid duringthis heating step as the supercritical fluid is vented off, and with thereactor's temperature and pressure being slowly reduced to over thecourse of the heating to become ambient temperature and atmosphereicpressure during the steady drying. As the supercritical CO₂ is ventedoff it is replaced with a nitrogen atmosphere in order to avoid damagingthe SAPH by oxidation. Traditional heat treatments typically require theintroduction of another solvent to aid in the extraction of benzene orother unwanted polymerization solvents. This step is unnecessary due tothe practice of the present invention and is yet another benefitthereof. In certain embodiments, the crosslinked SAPH of the presentinvention is exposed to heat in the reaction chamber at from about 80°C. to about 130° C.; or from about 90° C. to about 120° C. It isdesirable that the treatment temperatures be maintained below the glasstransition temperature of the SAPH, so that the SAPH does notagglomerate during heating, which in the case of the most preferredembodiment of the present invention would be a temperature not to exceed102° C. The duration of the heat treatment of the SAPH of the presentinvention is from 2 minutes to 5 hours, relatively long treatment timesbeing suitable at 80° C. and very short ones at no more than 102° C. Ifthe crosslinked SAPH is heated for too long a time, its swelling ratioin aqueous systems is reduced, and can fall to virtually 0, because thepolymer is then no longer swellable.

Exemplary Drying Method:

After heat treatment the hydrogel particles are subjected to dryingconditions to remove any remaining polymerization medium, carbondioxide, volatile monomers and low molecular weight oligomers,dispersing liquid, surfactants, residual solvent and substantially allof the unconsumed water. Preferred dryers are fluidized beds or beltdryers. Alternatively, a drum dryer may be used. Such techniquesespecially those assisted by vacuum systems are well known in the art.The optimal temperature at which the drying takes place is a temperaturehigh enough such that any remaining: polymerization medium and liquid,including water; modifiers, surfactants and any optional solvents, areremoved in a reasonable time period. The drying temperature should behigh enough to remove any and all anticipated volatiles, but not so highas to cause degradation of the SAPH material; i.e., ideally not toexceed the SAPH material's glass transition temperature. Desirably, theambient temperature of the SAPH particles of the present inventionduring drying is always maintained at about 50° C. or greater; at about75° C. or greater; at about 90° C. or greater; or at about 100° C.However, the drying temperature for the SAPH of the most preferredembodiment of this invention shall always remain just below its glasstransition temperature being less than 102° C. The drying time should besufficient to remove substantially all of the remaining unwantedreaction components, water and any undesirable volatile impurities.Preferably, a minimum time for drying is at least 10 minutes, with atleast 15 minutes being preferred. Preferably, the drying time is 60 minor less, with 25 min or less being more preferred. In certainembodiments, drying is performed under conditions such that water, andoptional solvent, volatilizing away from the absorbent resin particlesis maximally removed. Such removal can be maximally achieved by vacuumtechniques or by passing inert gases such as nitrogen or dehumidifiedheated air over or through the layers of resin particles. In certainembodiments, drying occurs in dryers where air heated at from about 70to 90° C. is blown through or over layers of the resin particles undervacuum. Exemplary dryers useful in methods of the invention include, forexample, fluidized beds, belt dryers, or drum dryers. In any event, thedrying time should be sufficient to remove any remaining volatiles tolevels below the acceptable exposure limits as an ingestible material assuch are established by jurisdictional regulatory authorities.

Moisture Content:

After drying, in certain embodiments of the invention the moisturecontent of the SAPH material between zero and about 20 weight percent;less than about 20 weight percent; less than about 10 weight percent; orless than about 5 weight percent. Therefore, immediately upon drying andcooling to room temperature, a quality assurance sample is removed fromthe batch based on SQL protocols, then the SAPH material of the presentinvention is wrapped in moisture barrier method, preferably adouble-lined container and sealed along with an anhydrous moisturebarrier pack (as are commonly used by those in the art) to protectagainst moisture accretion. The containers should not be reopened untilready for further manufacturing processing uses.

Exemplary SAPH Compositions:

SAPH particles produced according to the described modified inversepolymerization method using supercritical conditions in thepolymerization medium of the present invention have exceptionally lowlevels of: a) residual monomers, residual low molecular weightoligomers; (see Table 3 Residual Monomer), b) residual solvent, (seeTable 4 Residual Solvent and Volatiles), and c) heavy metals—especiallythe four toxic heavy metals most closely regulated; being arsenic,cadmium, lead and mercury (see Table 5 Residual Metals). A considerableadvantage of the present manufacturing process is that the solvation andpurification are conducted simultaneously as the excess monomers,volatiles and heavy metals are preferentially and selectively suspendedin the supercritical carbon dioxide phase; and are subsequently taken upand removed upon venting of the carbon dioxide. Additionally, thisprocess allows for easy distillation and recycling of the solventmaterial which reduces costs and minimizes hazardous environmentalwastes. The final drying step completes the removal of any and allremaining volatiles; usually to levels below the detection limits of themost sensitive analytical equipment available.

Method of Purity Analysis

The purity of the SAPH of the present invention was analyzed by state ofthe art methods and protocols conducted by Bodycote Testing Grouplocated at their Health Science and Analytical Division, 9240 Santa FeSprings Road, Santa Fe Springs, Calif., 90670. The testing for each ofthe three classes of by-products was performed as follows (the resultsof these tests are found in tables 3, 4, and 5):

TABLE 2 Testing Summary. Material Class Analytical Method Monomers andOligomers Gas Chromatography/Flame Ionization Solvents and Organic GasChromatography/Mass Spectrometry Volatiles SOP 5030 Rev 5 MetalsInductively Coupled Plasma - Mass Spectrometry SOP 7040 Rev 9

TABLE 3 Residual Monomer Analysis Gas Chromotography/Flame IonizationFree Acrylic Acid Results 33.2 ppm Acrylamide Results 0.3 ppm Sample ID:Lot # PS 100-07-12-01-1

TABLE 3 Residual Solvent and Volatiles Analysis Volatiles AnalysisResidual Solvents by SOP 5030, Rev 5 Gas Chromatography/MassSpectrometry Parts per Million (·g/g) Lot # PS100-07-12-01-1 DetectionAnalyte Limit (ppm) Result 1,4-Dioxane 0.2 ND Acetone 0.2 NDAcetonitrile 0.2 ND Benzene 0.2 ND Chloroform 0.2 ND Ethanol 0.2 NDEthyl acetate 0.2 ND Ethyl ether 0.2 ND Freon-113 0.2 ND Heptane 0.2 NDHexane 0.2 ND Isopropanol 0.2 ND Isopropyl acetate 0.2 ND Methanol 0.2ND Methyl ethyl ketone 0.2 ND Methyl isobutyl ketone 0.2 ND Methyltert-butyl ether 0.2 ND Methylene chloride 0.2 ND Pyridine 0.2 NDTetrahydrofuran 0.2 ND Toluene 0.2 ND Trichloroethylene 0.2 ND

TABLE 4 Residual Heavy Metals Analysis. Metals Screen by SOP 7040, Rev 9Inductively Coupled Plasma - Mass Spectrometry Sample ID: SWELL PS-100,Lot# PS100-07-12-01-1 Metals of Greatest Regulatory Concern Arsenic,Cadmium, Lead, and Mercury ppm Detection Exposure Limit Max DailyExposure Limit (70 kg Person) (ug/g) Limit (ppm) (ug/kg bw/d) Limit (ug)Max Dose (ug) % of Limit Arsenic ND 0.01 0.050 N/A Cadmium ND 0.01 0.200Lead ND 0.01 0.150 Mercury 0.049 0.01 0.100 7.000 0.22 3.1% Other MetalsList of ppm Detection Metals (ug/g) Limit Aluminum 7.3 0.50 Antimony ND0.01 Barium 0.12 0.08 Beryllium ND 0.01 Bismuth ND 0.01 Boron ND 0.10Bromine ND 0.70 Calcium 19.00 10.00 Cerium ND 0.01 Cesium ND 0.01Chromium 0.076 0.01 Cobalt ND 0.01 Copper ND 0.04 Dysprosium ND 0.01Erbium ND 0.01 Europium ND 0.01 Gadolinium 0.072 0.01 Gallium ND 0.01Germanium ND 0.01 Gold ND 0.01 Hafnium ND 0.01 Holmium ND 0.01 Iodine1.70 0.01 Iridium ND 0.01 Iron 1.00 0.50 Lanthanum 0.052 0.03 Lithium0.034 0.01 Lutetium ND 0.02 Magnesium ND 8.00 Manganese 0.019 0.01Neodymium ND 0.01 Nickel 0.054 0.01 Niobium ND 0.01 Osmium ND 0.01Palladium ND 0.01 Phosphorus ND 3.00 Platinum ND 0.01 Potassium 230 2.00Praseodymium ND 0.01 Rhenium ND 0.01 Rhodium ND 0.01 Rubidium 0.029 0.01Ruthenium ND 0.01 Samarium ND 0.01 Selenium ND 1.00 Silver ND 0.01Sodium MATRIX Strontium ND 0.40 Tantalum ND 0.01 Tellurium ND 0.01Thallium ND 0.02 Thorium ND 0.01 Thulium ND 0.01 Tin ND 0.01 Titanium0.21 0.02 Tungsten ND 0.01 Uranium ND 0.01 Vanadium ND 0.02 Ytterbium ND0.01 Yttrium ND 0.01 Zinc ND 0.20 Zirconium 0.069 0.01

In one embodiment, the SAPH of the invention comprises an ultrapure SAPHmaterial in the form of a polyacrylic acid hydrogel lightly cross-linkedwith polyethylene glycol as a pre-meal temporary ingestible gastricbulking agent used to mitigate hunger. Particularly the SAPH of thepresent invention is useful as an ingestible weight-loss and weightmanagement means to aid in suppressing appetite and/or promoting afeeling of early satiety in persons seeking to reduce their caloricintake, i.e., meal portion sizes, without a experiencing a residualfeeling of hunger. The further objects of the present invention includethe moderation of the gastric signaling mechanisms that acutely controlappetite and the sensation of fullness, and additionally for use as along term means of modifying eating behavior useful as a weightmanagement tool, thus providing an adjunct to assist persons seeking tolose and or manage their weight. Furthermore, the present invention isnot intended to be limited to human use, whereby veterinary uses arealso considered.

Exemplary Dosage and Administration

As recognized by those skilled in the art, since pure SAPH materials ofthe present invention are bio-inert, non-toxic, and meet all of thegenerally recognized as safe criteria; the practical and commerciallimitations for the intended use of this disclosure relate mostspecifically to the presence of unacceptable levels of post-manufactureconcentrations of impurities and contaminants commonly identified withinthe commercially available SAPH materials disclosed in the prior art.Governed by the specific limitations imposed by the prevailingjurisdictional regulatory bodies that monitor ingestion uses among eachof the three classes of common SAPH contaminants (residual monomers andresidual low molecular weight oligomers, residual solvents, and heavymetals), the threshold dosage amount of any SAPH material used in anyingestible form will need to be calculated based upon the regulatedresidual component found to be closest to its specific threshold maximumdaily exposure limit. Accordingly, the maximum acceptable amounts thatcan be ingested will necessarily be different based upon the specificregulations imposed on each impurity in each country as regulated bysuch country's governing authority. These rules and regulations changefrom time to time as new scientific, toxicological, epidemiological andenvironmental information is developed; and a consensus for settingappropriate exposure limitations is achieved. Therefore, those of skillin the art will recognize that amount of SAPH to be included in anydosage or delivery form may vary. However, those skilled in the art willappreciate the methods needed to be employed to manufacture deliverablegoods in each and all of the preferred embodiments herein that will bein compliance with each of these regulations for the disclosed purposesof the present invention. Basically, two preferred delivery means existfor the ingestible SAPH of the present invention; a) Non-combinationforms and b) Combination forms.

I. Exemplary Non-Combination Ingestible Forms:

The SAPH compositions of the invention are capable of being delivered inno-combination forms of the SAPH in filled capsules or gelcaps. The SAPHcompositions of the invention are safely, conveniently, andcost-effectively provided in such forms.

Using chewable tablets, powders or lozenges is contraindicated with thepresent invention for three reasons: First, since such delivery formswould potentially or deliberately expose the SAPH of the presentinvention to the salivary amylase and other degradation and digestivematerials located in the saliva of the mouth that act to prematurelyreduce the swelling ratio of the SAPH (prior to concomitant exposure andactivation by the co-ingested free water), the SAPH's bulking capacityin the stomach is reduced. Second, the SAPH of the present invention hasno taste whatsoever; and if tasted directly without the addition orpresence of flavoring agents or other modifiers as may be otherwiseprovided in combination and along with other more palatable ingredientsas are known by those skilled in the art, such taste establishes adisturbingly unpleasant sensation of poor palatability which reduces theuser-friendliness and therefore the user-compliance of the product.Third, the manufacture of tablets and lozenges involves high compressionmethods that: a) may require the addition of incompatible ingredients(pH, chemical instability or reactivity, etc.) used for tableting thatreduce the effectiveness of the SAPH, and b) can induce non-homogenousheating to the material being compressed. If such compression methodsheat any of crystalline domains of the SAPH beyond the glass transitionpoint, the SAPH domains so heated would be rendered functionally uselessand will reduce the efficiency of the material according to theprinciples and specific purposes of this invention.

The maximum single unit dose of the SAPH of the present inventionprovided in convenient capsule or gel cap form would be delivered in‘000’ capsules sizes, which is the largest standard commerciallyavailable capsule size. The milligram amount of the SAPH of the presentinvention that can be contained in a ‘000’ capsule is dependent upon theapparent bulk density of the SAPH of the present invention. The apparentbulk density is governed by the average particle size of the finalmaterial which can be modified as desired based on industry standardmethods of comminution and serial mesh sieving methods as describedherein. As an example, but not intended to be limiting, an SAPH of thepresent invention with an apparent bulk density of 0.8 g/cc wouldprovide approximately 1.0 g of SAPH in a ‘000’ capsule. Taken asrecommended as one or two capsules consumed with 6 to 12 oz of water percapsule 30 to 60 minutes before meals, the maximum daily exposure of aperson to the SAPH of the present invention would be calculated as 6 gper day. More preferably in the non-combination form, the SAPH of thepresent invention is provided in ‘00’ size capsules containing 750 mg ofSAPH with an apparent bulk density of 0.8 g/cc, thus delivering amaximum daily exposure of 4.5 g per day when taken as directed.Therefore, preferred dosage forms of both Non-Combination andCombination forms of the present invention in smaller amounts wouldcontain even fewer contaminants than the most concentrated form.

The hard capsule shells of the preferred embodiment are made from hardgelatin which is certified BSE-free and meets kosher standards; withfast-dissolving hard shells being most preferred. The more preferredembodiment uses vegetable shells, otherwise known by a variety ofcommercial names with one example being “Veggie Caps” as such areprovided by Capsuline® Inc., and other suppliers. The most preferredembodiment of the present invention when delivered as a non-combinationproduct is in the form of gel caps. Other dosage sizes can be easilyprepared by altering the apparent bulk density, adding excipients, orusing different size capsules or gel caps by incorporating standardmethods well known in the art.

As will be recognized by those skilled in the art, the concept ofnon-combination forms, as used by the applicant in the context of thedisclosure of the present invention, would not exclude the incorporationof small quantities of antimicrobial preservative agents, such asmethylparaben and or propylparaben. These preservatives are commonlyused in pharmaceutical and food products, and the addition of smallquantities of the preservatives does not interfere with the principles,practices and purposes of the present invention. When present, thesepreservatives can be added to the SAPH material of the present inventionin an amount typically less than 0.5% by weight, based on the totalweight of resinous crystals in the mixture.

Furthermore, capsules or gel caps filled with the SAPH of the presentinvention using standard capsule filling methods contain numerous voidsamong the SAPH particles which can be filled in with finely groundpowders of numerous desirable compositions. Examples of suchcompositions could include but without limitation; flavorings, activeingredients, nutritional ingredients, natural products, pharmaceuticalproducts, excipients, adjuvants, inert materials or other compositionsof matter that would modify, augment or otherwise enhance the commercialappeal of the product, broaden its usefulness, or provide someadditional, expanded or alternative benefit to a stand-alone SAPHmaterial of the present invention. In addition, the compositions mayoptionally include additional edible non-toxic ingredients asconventionally employed in medicinal dosage forms. Thus, thecompositions of the invention may optionally include one or moreexcipients in an amount within the range of from about 0.1% to about 99%by weight, examples of such, which are not intended to be limitinginclude: lactose, sugar, corn starch, modified corn starch, mannitol,sorbitol, and inorganic salts such as calcium carbonate and others.Other conventional ingredients which may optionally be present includeflavorings, preservatives, stabilizers, plasticizers, anti-adherents orsilica flow conditioners or glidants, such as Syloid brand silicondioxide as well as FD&C colors.

Furthermore, the present invention provided in the non-combination formof capsules or gel caps can be delivered in numerous unit dose ormulti-dose packagings well known in the art, included but withoutlimitation: a) bottles; b) blister-packs; c) foil pouches; d) packets;and other common packaging forms common to the sale of capsules or gelcaps. In addition, the present invention would carry a label and or apackage insert with all pertinent information as may be regulatorilymandated and or as may otherwise be commercially desirable. Additionalpackagings are envisioned and are not intended to be limited by thisdisclosure.

Clinical Data Validation

An exemplary embodiment of a SAPH of the present invention wasclinically evaluated in its non-combination form in a prospective,multi-site physician-directed open-label study of 100 patients. Thestudy was entitled “Use of a New Synthetic Gastric Bulking Agent forWeight Management.” The object of the 4-week study was to clinicallytest the utility of the present invention for use as a temporarypre-meal gastric bulking agent designed to maximally suppress appetitethus assisting in reducing appetite, reducing meal portions andsubsequently in assisting in weight management. The study's inclusionarycriteria were: a) Participants wishing to manage their weight; b) AgeRange: 18-75, and c) Participants who signed the Informed Consent Form,and the Model Release Form. The exclusionary criteria were: a)Participants who were non-compliant with testing or questionnaireregimens; b) Participants who were unable to tolerate taking the SAPH ofthe present invention the in Non-Combination form of 750 mg hard shellcapsules; c) Participants under 18 or over the age of 75; d)Participants with moderately severe co-morbid disease, that includescardiac, pulmonary, renal, gastro-intestinal, hepatic, or active cancer(this determination is subject to the study nurse and/or physician), ora history of GI surgery, and e) Participants with alcohol or drug abuseas determined by provider interviews or medical history.

Participants were placed on a diet and exercise program in addition toprotocol ingestion of the present invention. Information was collectedweekly for four weeks from each person regarding: a) certain personalinformation; b) diet and eating habits and behaviors; c) SAPHutilization; d) SAPH effectiveness; e) hunger status; f) meal portionsizes, and g) any associated side effects or adverse events. The SAPHcomposition of the invention that was utilized in the clinical trial iscurrently being sold under the tradename, PREE™. The recommended dietincluded a very-low amount of refined carbohydrates; although theoverall plan included equal amounts of total carbohydrates, fats, andproteins. The recommended use of carbohydrates involved the use ofcomplex carbohydrates, mostly green vegetables and grains, such as brownrice, with a repeated emphasis on extremely small amounts of refinedcarbohydrates, including soda, products containing sugar, corn syrup,wheat products, breads, pasta, potatoes, and similar foods. Each subjectwas counseled about these diet concepts throughout the study and againat the weekly check-in periods. Furthermore, participants were asked tocomply with a moderate exercise program.

Protocol:

1. Participants were recruited from those who were actively seekingmedically supervised weight-loss.

2. Participants met the inclusionary and exclusionary criteria andpassed a health-screening provided by the clinic.

3. Participants received pre and post study photos.

4. Participants were terminated from the study without prejudice if theyrepeatedly failed the compliance standards involving dosing, diet,exercise or failure to complete the study questionnaire.

5. Participants were required to sign the Informed Consent, indicatingthat they understood all aspects of this trial; and Model Release Formallowing use of their pictures.

6. The Study Coordinator instructed all Participants as to the protocoland other details of the study.

7. Participants were instructed precisely as to how and when to take thepresent invention during the course of this study and how to reportadverse reactions and any other pertinent information.

8. Participants were given a study folder containing the instructions, 4Questionnaires, and a one-month supply of present invention (bottlecontaining 90 capsules containing 750 mg of the SAPH of the presentinvention).

9. Participants were screened into the study by a physician or staffnurse.

10. Participants received instructions on how and when to complete thequestionnaire and where to fax the document weekly.

11. Participants were required to come back to the clinic every week forfour weeks to have their blood pressure, weight, body compositionchecked and complete the Questionnaire; and to obtain pre and post studyphotos.

12. Any adverse events were reported to the clinic or supervisingphysician immediately.

The study's two primary endpoints were: a) safety as documented by thelisting and rating of any and all side effects and related adverseevents; and b) the ability of the present invention to control appetite.The Study's two secondary endpoints were: a) the ability of the presentinvention to reduce meal portions consumed; and b) the degree of weightchange over the course of the study. The SAPH was provided in the formof 750 mg SAPH in 2-piece gelatin capsules. Patients were instructed totake one to two capsules 30 to 60 minutes before each meal with 6 to 12oz of water per capsule. Patients were provided with 90 capsules and astudy packet with a questionnaire to be filled out at baseline thenweekly for four weeks. The data was collected and analyzedindependently.

Analytical Methods:

1. Answers from the Questionnaire tools were coded from 1 to 5

2. Answers from the Questionnaires were subtracted from eachParticipants' baseline data to create the outcome measures

3. The responses for each question were analyzed using a t-test,Chi-Square test, Fisher's Exact Two-Tail t-test, or an ANOVA analysiswhere appropriate.

Categorical Analysis:

One-point differences were classified as “Minimal Improvement”,two-point differences as “Mild Improvement”, three-point differences as“Significant Improvement”, four-point differences as “DramaticImprovement”, and five-point differences as “Maximal Improvement”. Allcategories were analyzed using the Chi-Square test.

Statistical Significance:

Statistical significance ratings were: a) Highly Significant: p<0.05; b)Significant: p<0.10, and c) Statistical Trend: p<0.15

Preliminary Results:

Results from the study's first 24 participants with 2 weeks ofinformation as analyzed and reported below:

1. Responders: 95.8% ( 23/24)

2. Average Reduction in Portion Size: 21.0%

3. Average Rating of Hunger Control Effectiveness: 88.9%

4. Average Time to “feel” Fullness Effect: 36 minutes

5. Average Duration of Effect: 2.1 hours

6. Average Weight Loss: 4.6 pounds over the initial 2 week period

7. Doses Administered: >1500

8. Side-effects or Adverse Events Reported:

-   -   1. 4 patients with mild burping    -   2. 2 patients with mild constipation    -   3. 1 patient with moderate cramping sensation    -   4. 1 patient with mild chills    -   5. 1 patient with a mild headache

Final results and statistical analyses will be tabulated, statisticallyanalyzed and included in the final patent application.

The findings are summarized below, with reference to FIGS. 1-5:

1. Participant Statistics:

-   -   Average Age: 49    -   Average Beginning: BMI—30.5; Weight—183 lbs; Height—65 in    -   Average Ending: BMI—29.3; Weight—175 lbs; Height—65 in

2. Responders: 94.1%

3. Average 4-week Weight Loss: 7.6 lbs (4.2% of Body Mass)

4. Average Number of Capsules Taken per Day: 2.1

5. Average Reduction in Meal Portion Size: 34.3%

6. Average Rating of Hunger Control Effectiveness: 86.7%

7. Average Time to “feel” Fullness Effect: 33 minutes

8. Average Duration of “Fullness” Effect: 2.5 hours

9. Total Doses Administered: >2,000

10. Total Incidence of Side-effects: 3.6%; Adverse Events: None

Clinical trial participants were asked to rate their responses fromPREE's effects at each of breakfast, lunch and dinner (FIG. 1). PREE™generated a sensation of fullness or early satiety 94.1% of the time. In5.9% of meals, patients described that “No Effect” was noted. Inaddition to simply feeling a sense of fullness or early satiety withmeals, participants were asked to provide an overall combined score forPREE™ in terms of its ability to reduce meal portions and control hungerat each of the three meals daily, combined with an ability to translatethese feelings into weight loss (FIG. 2).

Of the 94.1% of participants that experienced a clinical effect fromPREE™ (see Graph 1) it was important to understand not only if an effectwas felt from PREE™ but whether or not that effect actually caused mealportions to be reduced; and if so, by how much. Responding participantswere asked to gauge the degree of their meal portion reduction in termsof the percentage decrease from their regular meal sizes (FIG. 3). Asshown in FIG. 3, 30.8% of the time meal portions were reduced by 10-24%.Equally, 30.8% of the time meal portions were reduced by 25-49%, withportion sizes reduced by 50% or more 38.5% of the time. The average mealportion reduction as reported in this study was 34.3%.

One of the most important findings of this or any clinical study is thedetermination of side effects and the recording of any study-relatedadverse events. FIG. 4 shows the incidence of occurrence of all studyrelated side effects. Of importance, no adverse events were reportedduring the study. Participants were also asked to report all sideeffects that they could relate to taking PREE™. A total of 3.6% of mealswere accompanied with some form of side effect. Participants were askedto rate the effects on a five point scale ranging from 1 (no effect) to5 (very severe). One person reported bloating rated at a “4” when taking2 capsules 3 times daily before meals. No other side effects were ratedhigher than 3 (moderate). Slight belching for a few minutes as thecapsules dissolved (within 10 minutes of ingestion) was the most commonside effect reported. Occasionally, these burps were accompanied with anunpleasant taste rated no more than 2 (mild).

The ability for PREE™ to assist participants in losing weight was alsomeasured. As can be seen in FIG. 5, participants lost an average of 1.9pounds per week, with an average weight loss of 7.6 pounds over the4-week study. Most weight management experts agree that if weight islost too rapidly it will generally not be sustainable. Therefore, mostrecommend that people lose weight more slowly—generally in the range of1 to 2 pounds per week so that the weight that comes off can stay off.

The SAPH compositions of the invention are designed and efficacious forhelping individuals lose weight sensibly and progressively withoutfeeling hungry or deprived in the process.

II. Exemplary Combination Ingestible Forms:

The SAPH of the present invention is highly adaptable and can beflexibly, multiply and alternatively incorporated into numerous usefulingestible forms when combined with other ingestible materials,components and ingredients. The specific purpose which combines the SAPHof the present invention with other ingestible materials would be toprovide a weight loss and or weight management dimension to the othermaterial(s) incorporated into the ingestible form which they alone wouldotherwise lack or alternatively not maximally provide a hungersuppression capability.

As will be appreciated by those skilled in the art, the SAPH of thepresent invention is a resinous material that exhibits an increasinglygranular texture with increasing particle size. One primary object ofthe present invention, which can be optionally incorporated intocombination forms, will be to mitigate the granularity of larger sizedparticles of the material by a softening means. Such means willpreferably occur through the use of a final hydrating step whereby theresinous SAPH material form can be quickly washed, sprayed or misted byan aqueous solution, which is preferably comprised of tap water and morepreferably by distilled water, and most preferably by flavored water,very briefly to soften the material, but in far less time than to allowfor any substantial degree of swelling. The contact time of the SAPHwill range from 1 second to 1 minute, depending on the original particlesize selected and the degree of softening desired. Of note, thoseskilled in the art will recognize that the softening occurs at theexpense of the swelling ratio, which will need to be accounted for inthe final delivery form. More preferably the dry resin can be mixed ortumbled in an aqueous mist of precisely measured amount of water withvigorous mixing to ensure contact all of the particles with the watercontent and to allow a controlled amount of softening. Most preferablyat the completion of the drying step, the temperature will be lowered to30° C. as the nitrogen atmosphere is replaced with humidified air andadmixed with the SAPH material until softening occurs. The timing forthe air mixing will preferably range from 1 second to 3 minutes, morepreferably from 3 minutes to 1 minute, and most preferably less than 1minute depending upon the average particle size and the desired degreeof softening. The thus softened resinous SAPH of the present inventioncan then be incorporated into various applications, for example mixes,food bases and many other final forms, some further examples are listedbelow, and some of which are more responsive to the needs of a softenedSAPH, most assuredly in those applications where the SAPH is exposed tothe mastication actions of the mouth and is subsequently ingested. Suchforms would include by example, but not limited to: cookies, bakedgoods, certain confectioneries, pressed bars, and other similar deliverymeans as are well known by those skilled in the art where a granulartexture of unsoftened material would be commercially undesirable.

In order to further illustrate the adaptability of the SAPH of thepresent invention as a combination ingestible form as well as theadvantages thereof, the following more specific examples are given.These examples describe a number of such uses as such are anticipated bythe applicant and can be anticipated by those skilled in the art. Theexamples are not intended to be a complete list. The examples areintended to be illustrative only of the principles and practices of thisinvention and are therefore not intended and are understood to in no waylimit the scope of the present invention as can be interpreted by themeanings disclosed herein.

EXAMPLE III SAPH Composition

Capsules or gel caps filled with the SAPH of the present invention usingstandard capsule filling methods contain numerous voids among the SAPHparticles which can be filled in with finely ground powders of numerousdesirable compositions. Examples of such compositions could include butwithout limitation; flavorings, active ingredients, nutritionalingredients, natural products, pharmaceutical products, excipients,adjuvants, inert materials or other compositions of matter that wouldmodify, augment or otherwise enhance the commercial appeal of theproduct, broaden its usefulness, or provide some additional, expanded oralternative benefit to a stand-alone SAPH material of the presentinvention. In addition, the compositions may optionally includeadditional edible non-toxic ingredients as conventionally employed inmedicinal dosage forms. Thus, the compositions of the invention mayoptionally include one or more excipients in an amount within the rangeof from about 0.1% to about 99% by weight, examples of such, which arenot intended to be limiting include: lactose, sugar, corn starch,modified corn starch, mannitol, sorbitol, and inorganic salts such ascalcium carbonate and others. Other conventional ingredients which mayoptionally be present include flavorings, preservatives, stabilizers,plasticizers, anti-adherents or silica flow conditioners or glidants,such as Syloid brand silicon dioxide as well as FD&C colors.

Quite unexpectedly, during Applicant's experimentation with numerousfilling agents for encapsulation, a novel reaction that has never beendescribed was observed through the mixing of a unique combination ofwhat was previously believed to be inert ingredients. When the SAPH ofExample 1 or II is mixed with stearic acid, magnesium stearate and talc,the resultant mixture imparts a substantial improvement inwater-swelling characteristics to the SAPH that was heretofore unknownand undescribed. The combination mixture demonstrates a substantialincrease in final particle size by 10% to 100% with improved turgor,color, buffering and other physical and chemical characteristicsdesirable of an ingestible SAPH designed for use as a gastric bulkingagent. Furthermore, the addition of these ingredients improves theflowability of the SAPH material for ease of capsule filling at reducedcosts.

In an exemplary embodiment, the SAPH mixture comprises from about 50% toabout 99% by weight of SAPH. In certain embodiment the SAPH mixturecomprises at least about 80.00%; at least about 90.00%; or about 92.59%by weight of SAPH.

In another exemplary embodiment, the SAPH mixture also comprises fromabout 0.01% to about 20.00% by weight of stearic acid. In certainembodiments the SAPH mixture comprises at least about 0.10%; at leastabout 1.00%; or at least about 2.78% by weight of stearic acid.

In still another exemplary embodiment, the SAPH mixture also comprisesfrom about 0.01% to about 10.00% by weight of magnesium stearate. Incertain embodiments the SAPH mixture comprises at least about 0.10%; atleast about 1.00%; or about 1.85% by weight of magnesium stearate.

In another exemplary embodiment, the SAPH mixture also comprises fromabout 0.01% to about 20.00% by weight of talc. In certain embodimentsthe SAPH mixture comprises at least about 0.01%; at least about 1.00%;or at least about 2.78% by weight of talc.

In a preferred embodiment, the ratio of the three excipient ingredientsin the SAPH mixture is 3:2:3 parts of stearic acid, magnesium stearateand talc respectively. Without being limited to any particular theory,it is hypothesized that the particular ratio of ingredients directlyaffects the swell-properties of the mixture. However, because theinvention relates to an unpredictable art, the synergistic interactionof the ingredients could not have been predicted.

The excipient materials of the present invention are blended togethersequentially in a standard pharmaceutical mixer with a method well knownto those skilled in the art. The mixing is accomplished in two stages.The first preblend is comprised of the SAPH mixed together with thestearic acid and magnesium stearate. The talc is added into the mixtureas a second preblend and the resultant combination of all fouringredients is mixed until it is homogenous ranging from about 2 toabout 20 minutes. The mixing is performed at room temperature andpressure under dehumidified air.

In addition to the usefulness of the SAPH mixture in a non-combinationcapsular form, the SAPH mixture of the present invention can beeffectively used in any of the other forms described herein. Bypremixing the ingredients as described above, then adding the SAPHmixture to nutritional bars, dietary supplement mixtures, foods, andnumerous other applications as would be readily appreciated by thoseskilled in the art, users can maximize the water-swellingcharacteristics of the SAPH as desirable for these ingestibleapplications. In addition to the improved flowability and cost, themixture improves palatability, texture and flavor of the finalingestible product as well.

Crystalline excipients like those described herein are known to those ofskill in the art. Although stearic acid has been used as a processcontrol agent in the blending of metals, in its dry-powder crystallineforms, stearic acid or its magnesium salt are not known to interact withtalc, and certainly their particle interactions have not been previouslydescribed with any materials like the SAPH of the previously describedinvention. This synergistic ability to enhance the water-swellablecharacteristics of the SAPH in this instance is unprecedented, andcurrently remains unexplained from a dry chemistry perspective. See,Influence of stearic acid on mechanochemical reaction between Ti and BNpowders; Jung-Soo Byun, Jae-Hyeok Shim and Young Whan Cho.Nano-Materials Research Center, Korea Institute of Science andTechnology, Seoul 136-791, South Korea, which is incorporated herein byreference for all purposes.

1. Dietary Supplements.

Dietary supplements, as such are regulated in the United States by theUS Food and Drug Administration (FDA) and similar bodiesinternationally, are typically orally delivered forms that can containnumerous permutations and combinations of components selected from avariety of classes of active and or inactive ingredients including, butnot limited to: a) vitamins; b) minerals; c) herbs; d) extracts; e)pro-biotics; f) pro-hormones; g) enzymes; h) amino acids; i) proteins;j) lipids; k) carbohydrates; l) botanical, flower, root and or othernatural animal and plant products and derivatives; m) oils; n) seeds; o)fruits; p) excipients; q) adjuvants, r) flavorings; s) stabilizers; t)preservatives, u) spices; v) anti-oxidants, w) pH buffers, x)excipients; y) adjuvants, and numerous of other types andclassifications of materials, and ingredients as are well known by thoseskilled in the art.

The SAPH of the present invention can be supplied in combination witheach one or in any combination of these abovementioned materials andingredients. Preferably, the SAPH of the present invention beingcombined in capsule or gel cap form will vary from 0.01% to 99.99% SAPHweight percent, depending on the desired requirements of the finalproduct combination. Particle size of the SAPH can also be modulated asrequired.

Some of the specific use applications for these dietary supplementswould provide combinations of ingredients specifically formulated for:a) energy and metabolism; b) anti-aging; c) memory; d) athleticperformance and endurance; e) hair, skin and nail formulas; f) visionand eye formulas; g) bone and joint formulas; h) prostate formulas; i)erectile dysfunction; j) sleep; k) anxiety; l) women's health formulas;m) heart and circulation formulas; n) cold and flu formulas; o) generalwellbeing, and dozens of other remedies in formulations that wouldcontain components that are well known to those skilled in the art.

It is one of the primary objects of the present invention to combine theSAPH of the present invention with these traditional nutritionalsupplement ingredients to form the first specialty product line ofdietary supplements designed specifically for and commercially targetingthe weight loss/weight management market. The objective of this novelcombination product line will be to provide commercially reasonablesolutions for people who not only want nutritional supplementation, butalso want to simultaneously lose or manage their weight; but mostpreferably want to use a SAPH material to provide temporary pre-mealgastric bulking as a means to mediate their appetite and manage theirresidual hunger in order to comfortably reduce their caloric intake bydecreasing their portion size.

Finally, due to the polyelectrolyte structure of the SAPH of the presentinvention, stability studies need to be completed for each combinationto determine shelf life labeling prior to commercialization. If anyinteractions occur among the ingredients and the SAPH of the presentinvention that reduce the shelf life to less than a commerciallyreasonably threshold, various techniques that are well known in the artcan be applied to isolate the ingredients while combinationallyencapsulated on the shelf awaiting consumption. Such techniques thatextend the useful shelf life to commercially reasonable limits includebut are not limited to: coatings, microencapsulation, lipidation,partitioning, and others.

2. Meal Substitutes and Food Additives:

Commercially available meal substitutes are currently sold in many formsincluding: powders, puddings, cookies, shakes, or bars just to name afew. The SAPH of the present invention can be numerously incorporatedinto each category of meal substitute, quickly, easily andcost-effectively so long as the follow-on processing steps do notinvolve heating the material above the glass transition temperature ofthe SAPH which is 102.degree. C.—for the present invention. Furthermore,as a business methodology, the SAPH of the present invention could besupplied as in Example 1 above as a co-sale item to be purchased alongwith, in combination with, attached with, packaged with, or otherwisesold in a related fashion with the Meal Substitutes.

When commercially provided in the form of a powder, the SAPH of thepresent invention is most preferably formulated with anhydrouscolorants, sweeteners and flavorings that combine to make an attractiveand tasteful ingestible treat when mixed with water. The water can behot (as in cinnamon-apple flavored mixes, cocoa flavored mixes), or coldas desired. When the SAPH mixture is added to water, the SAPH materialrapidly absorbs the water to form a gel material which can be both funto make and pleasurable to eat. This would be especially important foruses envisioned with children. The consistency of the final product canbe varied according to the average particle size of the SAPH used andthe relative amount of water added. Drinks and shakes are made by addingultra-fine resinous SAPH crystals in the mix into an excess of water.The more water that is added produces a proportionally thinner resultingdrink. Larger grain SAPH in slightly less water will produce aconsistency ranging from thin mucilage to a thick pudding-like materialwhich can be individually determined by the user. The resultant mixturecan be consumed at room temperature or the mixture can be subsequentlychilled or heated to the point of boiling water as desired, so that thematerial will develop consistencies ranging from gelatin to tapiocapudding—only the mixture will not have the calorie content typicallyassociated with similarly-used commercially available products.Obviously, from Example 1 above, numerous nutritional, natural products,supplement ingredients and other additives can be included as desired toprovide a low-calorie, good tasting and nutritious meal substitute at alow cost that is fun and easy to make that has all of the advantages ofthe resent invention.

The SAPH of the present invention absorbs approximately 500 times g/gits weight in typical city tap water. Therefore, only small quantitiesof the material will need to be used to make many of the mealsubstitutes as described herein. A further advantage of this embodimentis the compact size, light weight and end-product volume of suchmixtures; which would be extremely beneficial for use by hikers,campers, climbers and recreationists; as well as in certain militaryexpeditionary and special forces applications for inclusion as forexample in compact packed rations that could contain energy formulasamong others.

3. Dietary Confectionaries and Candies:

The SAPH of the present invention can be incorporated into confectionaryand candies of all types and descriptions. Consumed with water, theresultant gastric bulking would reduce appetite thus limiting the desireto over consume these energy-dense, calorie-rich foods. Furthermore, asa business methodology, the SAPH of the present invention could besupplied as in Example 1 above as a co-sale item to be purchased alongwith, in combination with, attached with, packaged with, or otherwisesold in a related fashion with the Dietary Confectionaries and Candies.

4. Meal Plans:

Commercially available meal plans provide consumers with balancednutritional and calorie restricted foods. The problem with these plansremains hunger after consumption. The SAPH of the present inventioncould be incorporated into the substance of the prepared meals in thosedishes that did not require heating beyond 100° C. Alternately, as abusiness methodology, the SAPH of the present invention could besupplied as in Example 1 above as a co-sale item to be purchased alongwith, in combination with, attached with, packaged with, or otherwisesold in a related fashion with the Meal Plans.

5. Cookies and Other Baked Goods:

Commercially available cookies and other baked goods frequently aredusted with sugar-sprinkles or other toppings after the baking process.Similarly, the SAPH of the present invention can be applied to suchbaked goods after the heating cycle to promote early satiety and reducethe urge to over-consume these items. Furthermore, as a businessmethodology, the SAPH of the present invention could be supplied as inExample 1 above as a co-sale item to be purchased along with, incombination with, attached with, packaged with, or otherwise sold in arelated fashion with the Cookies and other Baked Goods.

6. Nutrition (“Power”) Bars:

Commercially available nutrition bars, as such term is well understoodby those skilled in the art, are typically lightly compressed assembliesconsisting of recipes of whole foods, grains, fruits, nuts, honey,flavorings, sweeteners, vitamins, minerals and numerous otheringredients well known to those skilled in the art. Typically, thesebars are not heated and therefore provide a convenient delivery meansfor incorporating the SAPH of the present invention directly into thepre-compressed mix. Alternatively, as in Example 5 above, the SAPH ofthe present invention could be applied to the surface of the bars afterfabrication. The average particle size could be varied to providenumerous appearances, consistencies and granularity to meet a wide rangeof specifications. Furthermore, as a business methodology, the SAPH ofthe present invention could be supplied as in Example 1 above as aco-sale item to be purchased along with, in combination with, attachedwith, packaged with, or otherwise sold in a related fashion with theNutrition Bars.

7. Bottled Water Adjunct:

Despite the controversial findings in a recent study outlining thepotential health concerns inherent in drinking too much water, theprevailing scientific and medical opinion includes recommending theingestion of eight to ten 8 oz glasses of water per day for the averageperson. Per-capita bottled water consumption has risen almost 50 percentfrom 2001, to 27.6 gallons in 2006. Globally, the United States is thelargest consumer of bottled water, although on a per-capita basis, theUS was only 10^(th) in 2005. That year, Italians consumed almost twiceas much bottled water per capita as Americans. As a result, the bottledwater industry is currently posting sales in excess of $11 B annually.The diversity of bottled waters is increasing as well. Those skilled inthe art will recognize that the reference to bottled water will includeany and all suitable predominantly aqueous fluids that would promote theexpansion of the SAPH material in the gastric environment which couldinclude but not be limited to: coffee, tea, sodas, juices, flavoredwaters, activated waters, fortified waters, hydrogen-infused waters,mineral waters, energy and sports drinks, aqueous plant or animalextracts, aqueous biological drinks, carbonated and non-carbonateddrinks, and all other forms of bottled or canned liquids with apreponderance of water as the principle ingredient.

Many consumers purchase bottled water for health reasons. Many choose todrink bottled water in combination with weight management programs.Therefore, it is another primary object of the present invention toprovide the SAPH of the present invention in capsule or gel cap form asan integral part of the packaging of the bottled water product toprovide a convenient means of selling the two items in a value-addedsingle packaging concept. One or more capsules or gel caps can beincluded in numerous methods.

Preferably, one or more capsules could be conveniently and removablyaffixed to the external surface of the bottle with tape, a shrink-wrapor other similar means, in a location on the bottle where no shippingdamage could occur and potentially incorporating a conspicuous label todraw consumer attention to the presence of the co-packaged SAPHmaterial. More preferably, the capsules or gel caps could beincorporated into the sealing means of times used on the mouth of thebottle beneath the cap. Such a sealing means could contain aneasy-peel-off feature common to many such seals and would additionallysecurably include the capsule or gel cap in a waterproof reservoir meanson the undersurface of the seal or more preferrably on the dorsalsurface of the seal in a manner such that when peeled off, the capsuleor gel cap could be conveniently available for consumption along withthe bottled water. Most preferably, the capsule or gel cap could belocated in a small compartment that would be integrally located in thecap of the bottled water. The cap could preferably be configured with aliving hinge lid, provided as an integrally molded single-piece liddefining a small space where the capsule or gel cap could be contained.More preferably, the lid could be constructed as a snap-on, pop-offfeature defining a compartment for the caspule or gel cap beneath. Suchsnap-on lid would provide for easy automation loading of the capsule orgel cap. Such a lid could also be constructed with a small tab orgripping recess to allow for easy removal by the consumer.

In any event and through the use of any combinatorial packaging means,it is an object of the present invention to include the SAPH of thepresent invention in an easy, inexpensive manner to be co-located andintegrally packaged with a bottled water product. Furthermore, as abusiness methodology, the SAPH of the present invention could besupplied as a co-sale item to be purchased along with, in combinationwith, attached with, packaged with, or otherwise sold in a relatedfashion with the Bottled Water products.

8. Exercise and Fitness Equipment Adjunct:

In addition to other co-sale opportunities, the SAPH of the presentinvention could be included as a co-sale item with exercise and fitnessequipment. The capsules or gel caps could be sold directly with theequipment or alternately advertised simultaneously and offered as anafter-purchase sale through discounting means, via Internet continuitysales or other means for example, as such methods are well known bythose skilled in the art. Furthermore, as a business methodology, theSAPH of the present invention could be supplied as in Example 1 above asa co-sale item to be purchased along with, in combination with, attachedwith, packaged with, or otherwise sold in a related fashion with theExercise and Fitness Equipment.

9. Alcohol Absorbent:

In an unexpected discovery, the SAPH of the present invention has theuncanny capacity to absorb certain common alcoholic beverages, almost tothe same extent as pure water. The SAPH of the present invention wastested with numerous commercial brands of beer, wine and bottledspirits. Beer of all brands was well absorbed at swelling ratios of from250 to 400 times gram for gram. Clear colorless spirits, for examplevodka and gin were also well absorbed at 200 to 350 gram for gram—ifdiluted to less than 10% ethanol as in a glass with sufficient water.Colored spirits, as in various whiskies such as scotch, bourbon andothers, were less well absorbed to 100 to 200 times gram for gram,although if diluted sufficiently improved absorption would occur. Noabsorption occurred with any wines tested; irrespective of whether theywere red, white, sparkling or otherwise.

This discovery offers the novel opportunity to provide the SAPH of thepresent invention to be useful as a sobriety aid means. In addition toother outlets, such a product could be offered in liquor stores, barsand taverns and other locations where alcoholic beverages are sold toassist patrons with moderating consumption, and potentially reducingtheir blood alcohol levels despite equivalent alcohol volumeconsumption. As such, the SAPH of the present invention could becommercialized as an adjunctive means to promote more responsibledrinking behavior, especially with respect to driving after drinking.

A second benefit of this sobriety aid application would be the earlysatiety feature of entrapping the alcoholic beverage in the stomach andthe subsequent inducement of the sense of fullness, thus limiting thesubsequent volume of ingested alcoholic beverage being consumed.Decreases in alcohol consumption would promote a reduction inalcoholism, increase traffic safety, reduce alcohol-related overdoses,and moderate the development of cirrhosis and liver disease. Thesebenefits would substantially reduce the overall societal morbidity,mortality and costs associated with alcohol consumption.

In certain additional embodiments, the invention comprises a method inwhich the SAPH of the present invention is used (i.e., administered orconsumed) over time, to cause the individual to accommodate to reducedsizes of ingested meal portions without feeling residual hunger. Suchbehavioral modification over time will have many beneficial effectsincluding but not limited to: a) sustainable weight loss; b) reducedfood wastage; c) saving money; c) improved self-esteem, and e) reducedhealth care costs. The use of the present invention to cause aprogressive change in perception of the required meal portion size istherefore another primary object of the present invention.

It is understood that the detailed examples and embodiments describedherein are given by way of example for illustrative purposes only, andare in no way considered to be limiting to the invention. Variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are included within the spirit and purview ofthis application and are considered within the scope of the appendedclaims. For example, the relative quantities of the ingredients may bevaried to optimize the desired effects, additional ingredients may beadded, and/or similar ingredients may be substituted for one or more ofthe ingredients described. Additional advantageous features andfunctionalities associated with the systems, methods, and processes ofthe present invention will be apparent from the appended claims.

1. A gastric bulking composition for oral delivery comprising at leastone of a crosslinked polycarboxylate homopolymer, a crosslinkedpolycarboxylate copolymer or combination thereof; and a pharmaceuticallyacceptable excipient.
 2. The gastric bulking composition of claim 1,wherein the polycarboxylate homopolymer or copolymer comprises at leastone of an ethylenically unsaturated carboxylic acid, an ethylenicallyunsaturated carboxylic acid anhydride, or acid or basic salts thereof.3. The gastric bulking composition of claim 1, wherein the crosslinkedpolycarboxylate homopolymer or copolymer comprises at least one of apolyacrylic acid, a polyacrylamide, or alkali salt thereof.
 4. Thegastric bulking composition of claim 2, wherein the homopolymercomprises a sodium salt of a polyacrylic acid.
 5. The gastric bulkingcomposition of claim 1, wherein the composition comprises from about 50%to about 99% by weight of a crosslinked polycarboxylate, and from about1% to about 10% by weight of L-Leucine.
 6. The gastric bulkingcomposition of claim 5, wherein the composition comprises from about 95%by weight of a crosslinked polycarboxylate, and about 5% by weight ofL-Leucine.
 7. A polymer hydrogel composition comprising a combination ofcrosslinked polycarboxylic acid, stearic acid, and magnesium stearate.8. The polymer hydrogel of claim 7, wherein the composition furthercomprises at least one of magnesium silicate, gelatin, glycerin or acombination thereof.
 9. The polymer hydrogel of claim 7, wherein thestearic acid, magnesium stearate, and talc are present at a relativeratio of 3:2:3, respectively.
 10. The polymer hydrogel of claim 8,wherein the composition comprises from about 50% to about 99% by weightof the crosslinked polycarboxylic acid, from about 0.01% to about 20.00%by weight of stearic acid, from about 0.01% to about 10.00% by weight ofmagnesium stearate, and from about 0.01% to about 20.00% by weight ofmagnesium silicate.
 11. The polymer hydrogel of claim 10, wherein thecrosslinked polycarboxylic acid comprises particles having a pluralityof size distributions.
 12. The polymer hydrogel of claim 10, wherein thepolycarboxylic acid further comprises at least one comonomer.
 13. Thepolymer hydrogel of claim 12, wherein the comonomer comprises at leastone of an acrylamide, an acrylonitrile, a vinyl pyrrolidone, a vinylsulphonic acid or a salt thereof, a cellulosic monomer, a modifiedcellulosic monomer, a polyvinyl alcohol, a starch hydrolyzate orcombination thereof.
 14. The polymer hydrogel of claim 13, wherein thecomonomer comprises greater than about 5% by weight of the monomermixture.
 15. The polymer hydrogel of claim 13, wherein the comonomercomprises greater than about 10% by weight of the monomer mixture. 16.The polymer hydrogel of claim 7, wherein the composition furthercomprises at least one of a (poly)vinyl or non-vinyl crosslinker. 17.The polymer hydrogel of claim 16, wherein the (poly)vinyl or non-vinylcrosslinker are selected from the group consisting of glycerin,polyglycols, ethylene glycol, digylcidyl ether, and aliamines.
 18. Thegastric bulking composition of claim 1, wherein the copolymer isselected from the group consisting of an acrylamide, an acrylonitrile, avinyl pyrrolidone, a vinyl sulphonic acid or a salt thereof, acellulosic monomer, a modified cellulosic monomer, a polyvinyl alcohol,a starch hydrolyzate, and combinations thereof.
 19. A method ofmodulating appetite in an individual comprising administering aneffective amount of the composition of claim 1 in a unitary dosage formprior to a meal, wherein the composition is effective in promoting earlysatiety.
 20. A method of forming a bulking agent comprising: (i)polymerizing a monomer or a monomer mixture in a polymerization mixturecomprising: (a) at least one ethylenically unsaturatedcarboxyl-containing monomer, (b) at least one crosslinking agent, and(c) a polymerization medium consisting of a supercritical fluid solvent,wherein the mixture forms a crosslinked hydrogel; (ii) venting thesupercritical fluid solvent; (iii) comminuting the hydrogel to resinousparticles; (iv) drying the hydrogel to form resinous crystals; (v)sorting the resinous crystals; and (vi) heating the resinous crystals.